CN102030750A - Novel tetrahydro-1H-pyrido [4,3-b] indole derivatives as CB1' receptor ligands - Google Patents

Novel tetrahydro-1H-pyrido [4,3-b] indole derivatives as CB1' receptor ligands Download PDF

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CN102030750A
CN102030750A CN2010105223008A CN201010522300A CN102030750A CN 102030750 A CN102030750 A CN 102030750A CN 2010105223008 A CN2010105223008 A CN 2010105223008A CN 201010522300 A CN201010522300 A CN 201010522300A CN 102030750 A CN102030750 A CN 102030750A
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tetrahydrochysene
pyrido
indoles
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methyl
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程云星
麦罗斯劳·托马萨维斯基
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AstraZeneca AB
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Abstract

Compounds of Formulae I, or pharmaceutically acceptable salts thereof: wherein R<1>, R<2> and R<3> are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

New tetrahydrochysene-1H-pyrido [4,3-b] indole derivatives as the CB1 receptors ligand
The application of this division be the exercise question submitted on March 17th, 2006 for the application number of " as new tetrahydrochysene-1H-pyrido [4,3-b] indole derivatives of CB1 receptors ligand " be dividing an application of 200680016809.7 application for a patent for invention.
According to 35U.S.C. § 119 (a)-(d), the right of priority that the Sweden that the application requires on March 22nd, 2005 to submit to applies for No.0500654-9, this application integral body is incorporated herein by reference.
Technical field
The present invention relates to therapeutic compound, comprise pharmaceutical composition, the Preparation Method And The Use of these compounds.Particularly, the present invention relates to effectively to treat the compound of pain (pain), cancer (cancer), multiple sclerosis (multiple sclerosis), Parkinson disease (Parkinson ' s disease), Huntington Chorea (Huntington ' s chorea), Alzheimer disease (Alzheimer ' s disease), anxiety disorder (anxietydisorder), gastrointestinal tract disease (gastrointestinal disorder) and/or cardiovascular disorder (cardiovascular disorder).
Background technology
To too much after deliberation year of pain control (pain management).And, know Cannabined receptor (for example, CB 1Acceptor, CB 2Acceptor) part comprises agonist, antagonist and inverse agonist, by with CB 1And/or CB 2Acceptor interaction alleviates the pain in the various animal models.Usually, CB 1Acceptor mastery ground (predominately) is positioned at central nervous system, and CB 2Acceptor mainly is positioned at periphery (periphery), and mainly is subject to and derives from immune cell and tissue.
Although CB 1Receptor stimulant, for example Δ 9-tetrahydrocannabinol (Δ 9-THC) and arachidonic acid amides (anadamide), can be used for the anti-nociception model of animal, but they often produce undesirable CNS side effect, for example psychoactive side effect, abuse potential, drug dependence and tolerance etc.Known these undesirable side effects are by the CB that is arranged in CNS 1Acceptor mediates.Yet a series of evidences show, act on the periphery position or have the CB that limited CNS exposes 1Agonist can be controlled the pain of the mankind or animal, and overall interior the distribution greatly improved.
Therefore, need new CB 1Receptors ligand, agonist for example, it can be used for pain management or treats other related symptoms or disease, and reduces undesirable CNS side effect or it is minimized.
Embodiment
The invention provides CB 1Receptors ligand, it can be used for treating pain and/or other relevant symptom or disease.
Term " C M-n" or " C M-nGroup " is meant any group with m～n carbon atom.
Term " alkyl " is meant and comprises the 1 saturated monovalence straight or branched alkyl to about 12 carbon atoms.The illustrative example of alkyl includes but not limited to C 1-6Alkyl, as methyl, ethyl, propyl group, sec.-propyl, 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group, the 2-methyl-1-butene base, 3-methyl isophthalic acid-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl group, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-1-pentene base, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl and hexyl, and longer alkyl are as heptyl and octyl group.Alkyl can be unsubstituted, also can be replaced by one or two suitable substituents.
Term " thiazolinyl " is meant to have at least one carbon-to-carbon double bond and comprise at least two monovalence straight or branched alkyl to about 12 carbon atoms.Two keys of thiazolinyl can be and another unsaturated group conjugation or unconjugated.Suitable thiazolinyl includes but not limited to C 2-6Thiazolinyl, as vinyl, allyl group, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethyl hexene base, 2-propyl group-crotyl, 4-(2-methyl-3-butylene)-pentenyl.Thiazolinyl can be unsubstituted, also can be replaced by one or two suitable substituents.
Term " cycloalkyl " is meant that comprising at least 3 saturated monovalencies to about 12 carbon atoms contains cyclic hydrocarbon radical.The example of cycloalkyl includes but not limited to C 3-7Cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, and saturated ring-type and two cyclic terpene alkene.Cycloalkyl can be unsubstituted, also can be replaced by one or two suitable substituents.Preferably, this cycloalkyl is monocycle or dicyclo.
Term " cycloalkenyl group " is meant to have at least one carbon-carbon double bond and contain at least 3 to containing cyclic hydrocarbon radical up to about the monovalence of 12 carbon atoms.
Term " aryl " be meant have one or more tool aromaticity (for example 4n+2 delocalized electron) many unsaturated carbocyclics and contain 5, the monovalence alkyl of about 14 carbon atoms at the most, wherein connect base (radical) and be positioned on the carbon of aromatic nucleus.
Term " heterocycle " be meant the multivalence heteroatoms that has among one or more N of being independently selected from, O, P and the S as comprise at least 3 in the part of ring structure and (one or more) ring, about 20 atoms contains ring structure or molecule at the most.Heterocycle can be saturated or undersaturated, contains one or more pairs of keys, and heterocycle can contain a more than ring.When heterocycle contains more than when ring, ring can be condensed or uncondensed.Fused rings typically refers to shares at least two rings of two atoms therebetween.Heterocycle can have or not have aromaticity.
Term " heteroaromatic group " be meant comprise in the multivalence heteroatoms that has among one or more N of being independently selected from, O, P and the S and (one or more) ring at least 3, at the most about 20 carbon atoms contain ring structure or molecule, wherein this contains ring structure or molecule has aromaticity (for example 4n+2 delocalized electron).
Term " heterocyclic group (heterocyclic group) ", " heterocyclic moiety (heterocyclic moiety) ", " heterocycle (heterocyclic) " or " heterocycle is (heterocyclo) also " are meant by heterocycle by removing the group that its one or more hydrogen are derived and obtained.
Term " heterocyclic radical (heterocyclyl) " is meant by removing on the heterocycle that a hydrogen is derived and the univalent perssad that obtains.
Term " inferior heterocyclic radical " is meant that by heterocycle by removing the divalent group that two hydrogen is derived and obtained, it is used for two structures are linked together.
Term " heteroaryl " is meant the heterocyclic radical with aromaticity.
Term " Heterocyclylalkyl " is meant and comprises carbon and hydrogen atom and at least one, preferred 1～3 heteroatomic saturated monocycle or many ring that is selected from nitrogen, oxygen and sulphur.The example of Heterocyclylalkyl comprises pyrrolidyl, pyrrolidino, piperidyl, piperidino-(1-position only), piperazinyl, Piperazino, morpholinyl, morpholino, parathiazan base, parathiazan generation and pyranyl.Heterocyclylalkyl can be unsubstituted, also can be replaced by one or two suitable substituents.Preferably, this Heterocyclylalkyl is monocycle or dicyclo, monocycle more preferably, and wherein this ring comprises 3～6 carbon atoms and 1～3 heteroatoms, is referred to as C 3-6Heterocyclylalkyl.
Term " inferior heteroaryl " is meant the inferior heterocyclic radical with aromaticity.
Term " inferior Heterocyclylalkyl " is meant the inferior heterocyclic radical with aromaticity.
Term " hexa-atomic " is meant the group with the ring that contains six annular atomses.
Term " five yuan " is meant the group with the ring that contains five annular atomses.
Pentacyclic heteroaryl is meant the heteroaryl with the ring that contains five annular atomses, and wherein 1,2 or 3 annular atoms is independently selected from N, O and S.
Exemplary pentacyclic heteroaryl be thienyl, furyl, pyrryl, imidazolyl, thiazolyl,
Figure BSA00000321451200031
Azoles base, pyrazolyl, isothiazolyl, different
Figure BSA00000321451200032
Azoles base, 1,2,3-triazoles base, tetrazyl, 1,2,3-thiadiazolyl group, 1,2,3-
Figure BSA00000321451200033
Di azoly, 1,2,4-triazolyl, 1,2,4-thiadiazolyl group, 1,2,4-
Figure BSA00000321451200034
Di azoly, 1,3,4-triazolyl, 1,3,4-thiadiazolyl group and 1,3,4-
Figure BSA00000321451200041
Di azoly.
The heteroaryl of six-ring is meant the heteroaryl with the ring that contains six annular atomses, and wherein 1,2 or 3 annular atoms is independently selected from N, O and S.
The heteroaryl of exemplary six-ring is pyridyl, pyrazinyl, pyrimidyl, triazinyl and pyridazinyl.
Heterocycle comprises, monocyclic heterocycles for example, for example: aziridine (aziridine), oxyethane, thiirane, azetidine, trimethylene oxide, Thietane (thietane), tetramethyleneimine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, tetramethylene sulfone, 2, the 3-dihydrofuran, 2, the 5-dihydrofuran, tetrahydrofuran (THF), tetramethylene sulfide, piperidines, 1,2,3,6-tetrahydrochysene-pyridine, piperazine, morpholine, parathiazan, pyrans, thiapyran, 2, the 3-dihydropyrane, tetrahydropyrans, 1, the 4-dihydropyridine, 1, the 4-dioxane, 1, the 3-dioxane, dioxane, high piperidines (homopiperidine), 2,3,4,7-tetrahydrochysene-1H-azepine
Figure BSA00000321451200042
(2,3,4,7-tetrahydrochysene-1H-azepine), high piperazine (homopiperazine), 1, the 3-Dioxepane (1,3-dioxepane), 4,7-dihydro-1,3-two oxa-s
Figure BSA00000321451200043
(4,7-dihydro-1,3-dioxepin) and oxepane (hexamethylene oxide).
In addition, heterocycle comprises aromatic heterocycle, for example pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furans, furazan, pyrroles, imidazoles, thiazole,
Figure BSA00000321451200044
Azoles, pyrazoles, isothiazole, different
Figure BSA00000321451200045
Azoles, 1,2,3-triazoles, tetrazolium, 1,2,3-thiadiazoles, 1,2,3-
Figure BSA00000321451200046
Diazole, 1,2,4-triazole, 1,2,4-thiadiazoles, 1,2,4-
Figure BSA00000321451200047
Diazole, 1,3,4-triazole, 1,3,4-thiadiazoles and 1,3,4- Diazole.
In addition, heterocycle comprises many ring heterocycles, for example indoles, indoline, xylylenimine, quinoline, tetrahydroquinoline, isoquinoline 99.9, tetrahydroisoquinoline, 1,4-benzo two
Figure BSA00000321451200049
Alkane (1,4-benzodioxan), tonka bean camphor, melilotine, cumarone, 2,3-Dihydrobenzofuranes, isobenzofuran, chromene, chroman, heterochromatic full, xanthene, fen thiophene
Figure BSA000003214512000410
Thianthrene, indolizine, isoindole, indazole, purine, phthalazines, naphthyridines, quinoxaline, quinazoline, cinnolines, pteridine, phenanthridines, perimidine (perimidine), phenanthroline, azophenlyene, thiodiphenylamine, fen
Figure BSA000003214512000411
Piperazine, 1, the 2-benzisoxa Azoles, thionaphthene, benzo
Figure BSA000003214512000413
Azoles, benzothiazole, benzoglyoxaline, benzotriazole, Thioxanthine (thioxanthine), carbazole, carboline, acridine, tetramethyleneimine scholar pyridine (pyrolizidine) and quinolixiding (quinolizidine).
Except above-mentioned many ring heterocycles, heterocycle also comprises so many rings heterocycle, the fused rings between wherein two or more rings comprise more than one by the public key of two rings and more than two by two atoms that ring is public.The example of this bridged heterocyclic comprises rubane (quinuclidine), diazabicyclo [2.2.1] heptane and 7-oxabicyclo [2.2.1] heptane.
Heterocyclic radical comprises for example monocyclic heterocycles base, for example: '-aziridino, Oxyranyle, the thiirane base, azetidinyl, oxetanyl, the Thietane base, pyrrolidyl, pyrrolinyl, imidazolidyl, pyrazolidyl, pyrazolinyl, dioxolanyl, the tetramethylene sulfone base, 2,3-dihydrofuran base, 2,5-dihydrofuran base, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, 1,2,3,6-tetrahydrochysene-pyridyl, piperazinyl, morpholinyl, the parathiazan base, pyranyl, the thiapyran base, 2, the 3-dihydro pyranyl, THP trtrahydropyranyl, 1,4-dihydropyridine base, 1,4-dioxane base, 1,3-dioxane base, the dioxane base, homopiperidinyl, 2,3,4,7-tetrahydrochysene-1H-azepine
Figure BSA00000321451200051
Basic, high piperazinyl, 1,3-Dioxepane base, 4,7-dihydro-1,3-two oxa-s
Figure BSA00000321451200052
Base and oxepane alkyl.
In addition, heterocyclic radical comprises aromatic heterocyclic radical or heteroaryl, for example pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thienyl, furyl, furazan base, pyrryl, imidazolyl, thiazolyl,
Figure BSA00000321451200053
Azoles base, pyrazolyl, isothiazolyl, different Azoles base, 1,2,3-triazoles base, tetrazyl, 1,2,3-thiadiazolyl group, 1,2,3-
Figure BSA00000321451200055
Di azoly, 1,2,4-triazolyl, 1,2,4-thiadiazolyl group, 1,2,4- Di azoly, 1,3,4-triazolyl, 1,3,4-thiadiazolyl group and 1,3,4-
Figure BSA00000321451200057
Di azoly.
In addition, heterocyclic radical comprises many ring heterocyclic radicals (comprise aromatics or non-aromatics), for example indyl, indolinyl, dihydro-iso indolyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, 1,4-benzo two
Figure BSA00000321451200058
Alkyl, tonka bean camphor base, melilotine base, benzofuryl, 2,3-dihydro benzo furyl, isobenzofuran-base, chromenyl, chromanyl, different chromanyl, xanthenyl, fen thiophene
Figure BSA00000321451200059
Base, thianthrenyl, indolizine base, pseudoindoyl, indazolyl, purine radicals, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolines base, pteridyl, phenanthridinyl, perimidinyl, phenanthroline base, phenazinyl, phenothiazinyl, fen
Figure BSA000003214512000510
Piperazine base, 1, the 2-benzisoxa
Figure BSA000003214512000511
Azoles base, benzothienyl, benzo
Figure BSA000003214512000512
Azoles base, benzothiazolyl, benzimidazolyl-, benzotriazole base, Thioxanthine base, carbazyl, carbolinyl, acridyl, tetramethyleneimine scholar pyridine base and quinolixiding base.
Except above-mentioned many ring heterocyclic radicals, heterocyclic radical also comprises so many rings heterocyclic radical, the fused rings between wherein two or more rings comprise more than one by the public key of two rings and more than two by two atoms that ring is public.The example of this bridged heterocyclic base comprises quinuclidinyl, diazabicyclo [2.2.1] heptyl and 7-oxabicyclo [2.2.1] heptyl.
Term " alkoxyl group " is meant the group of general formula-O-R, and wherein R is selected from alkyl.Exemplary alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, isobutoxy, cyclo propyl methoxy, allyloxy and alkynes propoxy-.
Halogen comprises fluorine, chlorine, bromine and iodine.
" RT " or " rt " means room temperature.
On the one hand, embodiment of the present invention provide formula I compound, or its pharmacy acceptable salt, their diastereomer, enantiomer or its mixture:
Figure BSA00000321451200061
Wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8,-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl is optional to be selected from following group by one or more and to replace :-OR, R, NO 2,-CO 2H ,-CO 2-R;-SO 2-R; Halogen;-OH;-NH 2-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl;
R 4Be selected from nitrogenous C 3-9Heterocyclic radical and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclic radical can be chosen wantonly and is selected from following group by one or more and replace: C 1-6Alkyl, phenyl, C 1-6Alkoxyl group ,-NH 2,-OH, halo C 1-6Alkyl and halogen; And
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl.
Another embodiment of the present invention provides formula I compound, wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8,-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from C 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, and oxyethyl group ,-S (=O) 2CH 3, methyl, ethyl ,-NO 2,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl and C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, and oxyethyl group ,-S (=O) 2CH 3, methyl, ethyl ,-NO 2,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 4Be selected from nitrogenous C 3-9Heterocyclylalkyl and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclylalkyl can be chosen wantonly and is selected from following group by one or more and replace: methyl, ethyl, phenyl, methoxyl group, oxyethyl group ,-OH, trifluoromethyl and halogen; And
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, phenyl, benzyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-methyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-methyl; Hydroxyl-C 1-6Alkyl, methoxyl group-C 1-6Alkyl and oxyethyl group-C 1-6Alkyl.
Another embodiment of the present invention provides formula I compound, wherein
R 1Be selected from-C (=O)-R 4With-NH-C (=O)-R 5
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl, benzyl and C 3-5Heteroaryl-methyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl, benzyl and C 3-5Heteroaryl-methyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group ,-NO 2,-S (=O) 2CH 3, methyl, ethyl ,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-methyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-methyl and C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-methyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-methyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen;
R 4Be selected from piperidyl, piperazinyl and morpholinyl, wherein said piperidyl, piperazinyl and morpholinyl be optional to be selected from following group by one or more and to replace: methyl, ethyl, methoxyl group, oxyethyl group ,-OH, methylol, trifluoromethyl and halogen; And
R 9And R 10Be independently selected from :-H, C 1-6Alkyl and C 2-6Thiazolinyl.
An embodiment more of the present invention provides formula I compound, wherein
Figure BSA00000321451200091
R 2Be selected from methyl, ethyl, the 1-propyl group, the 2-propyl group, the 1-butyl, the 2-butyl, the tertiary butyl, allyl group ,-S (=O) 2-CH 3,-S (=O) 2-CH 2CH 3, 2-methoxy ethyl, tetrahydropyran-4-base-methyl, 1-sulfonyl propyl base, cyclopropyl alkylsulfonyl, phenyl, benzenesulfonyl, 2-(methoxycarbonyl)-benzenesulfonyl; 2-(hydroxycarbonyl group)-benzenesulfonyl, 1-methyl isophthalic acid H-imidazol-4 yl-alkylsulfonyl, 1H-imidazoles-1-base-alkylsulfonyl, (the 5-methyl is different
Figure BSA00000321451200101
Azoles-4-yl) alkylsulfonyl, morpholine-4-base carbonyl, 4-amino-phenyl ,-CH 2-C (=O)-N (CH 3) 2,-C (=O)-N (CH 3) 2,-S (=O) 2-N (CH 3) 2,-S (=O) 2-NHCH 2CH 3,-C (=O)-CH 2CH 2CH 3,-CH 2-C (=O)-OCH 3,-CH 2-C (=O)-OCH 2CH 3,-CH 2-CO 2H, benzyl, 4-aminobenzyl; the 4-nitrobenzyl, 4-methyl sulphonyl-benzyl, 4-methylthio group-benzyl; 4-acetylaminohydroxyphenylarsonic acid benzyl, 4-methoxyl group-benzyl, 4-oxyethyl group-benzyl; 2,6-difluorobenzyl, (6-chloro-1; 3-benzodioxole-5-yl) methyl, (5-ethoxy carbonyl)-furans-2-base-methyl, (2-methyl isophthalic acid; 3-thiazole-4-yl)-and methyl, (5-methyl-different
Figure BSA00000321451200102
Azoles-4-yl)-and methyl, pyridine-2-ylmethyl, cyclobutylmethyl and cyclopropyl methyl;
R 3Be selected from ethyl, sec.-propyl, propyl group, 2-methyl-propyl group; the 1-butyl, 1-amyl group, 1-ethanoyl-piperidin-4-yl, tetramethylene sulfide-3-base; the cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclobutyl; cyclopentyl, cyclohexyl, 4-tetrahydrochysene-2H-pyranyl, tetrahydrochysene-thiapyran-4-base; the 2-pyrimidyl, 1-imino-ethyl, 2-pyridyl; 3,4,5; 6-tetrahydropyridine-2-base, 3,4-dihydro-2 h-pyrrole-5-base; 2-pyridyl-methyl, 3-pyridylmethyl, 4-pyridylmethyl; 1-methyl-4-piperidyl, 4-piperidyl, (6-methyl-pyridine-2-yl) methyl; (2-ethyl-4-methyl isophthalic acid H-imidazoles-5-yl) methyl, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-ylmethyl; 1-ethyl-1H-pyrazoles-4-base, 1,3-dimethyl-1H-pyrazoles-5-base; (3-picoline-4-yl) methyl, 1,3-
Figure BSA00000321451200103
Azoles-2-ylmethyl, 1,3-
Figure BSA00000321451200104
Azoles-5-ylmethyl, 2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl, tetrahydrochysene-2H-pyrans-4-ylmethyl, 2-phenylethyl, 2-methoxy-benzyl, 3,3,3-trifluoro propyl, 2,2-two fluoro ethyls, 2-hydroxycyclopent base, (1-ethyl-3-methyl isophthalic acid H-pyrazoles-5-yl) methyl, 2,1,3-benzo
Figure BSA00000321451200105
Diazole-5-ylmethyl, 3-thienyl methyl, 2-trifluoromethyl-benzyl; the 3-methyl butyl, hexamethylene-3-alkene-1-ylmethyl, 2-fluoro-6-methoxy-benzyl; 2-phenyl-propyl group, 2-ethyl-butyl, cyclobutyl carbonyl; 2,2-difluoro propionyl, cyclopentylcarbonyl; tetrahydrochysene-2H-pyrans-4-base carbonyl, cyclopropyl carbonyl, propyl group carbonyl; N-ethylamino carbonyl, N-sec.-propyl aminocarboxyl, cyclopropyl alkylsulfonyl and ethylsulfonyl.
In another embodiment, R 3Be selected from ethyl, sec.-propyl, propyl group, 2-methyl-propyl group; the 1-butyl, 1-amyl group, 1-ethanoyl-piperidin-4-yl, tetramethylene sulfide-3-base; the cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclobutyl; cyclopentyl, cyclohexyl, 4-tetrahydrochysene-2H-pyranyl, tetrahydrochysene-thiapyran-4-base; the 2-pyrimidyl, 1-imino-ethyl, 2-pyridyl, 3; 4,5,6-tetrahydropyridine-2-base; 3,4-dihydro-2 h-pyrrole-5-base, 2-pyridyl-methyl; the 3-pyridylmethyl, 4-pyridylmethyl, 1-methyl 4-piperidyl; the 4-piperidyl, (6-methyl-pyridine-2-yl) methyl, (2-ethyl-4-methyl isophthalic acid H-imidazoles-5-yl) methyl; tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, tetrahydrofuran (THF)-3-ylmethyl; 1-ethyl-1H-pyrazoles-4-base, 1,3-dimethyl-1H-pyrazoles-5-base; (3-picoline-4-yl) methyl, 1,3-
Figure BSA00000321451200111
Azoles-2-ylmethyl, 1,3-
Figure BSA00000321451200112
Azoles-5-ylmethyl, 2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl, tetrahydrochysene-2H-pyrans-4-ylmethyl, 2-phenylethyl, 2-methoxy-benzyl, 3,3,3-trifluoro propyl, 2,2-two fluoro ethyls, 2-hydroxycyclopent base, (1-ethyl-3-methyl isophthalic acid H-pyrazoles-5-yl) methyl, 2,1,3-benzo
Figure BSA00000321451200113
Diazole-5-ylmethyl, 3-thienyl methyl, 2-trifluoromethyl-benzyl; the 3-methyl butyl, hexamethylene-3-alkene-1-ylmethyl, 2-fluoro-6-methoxy-benzyl; 2-phenyl-propyl group, 2-ethyl-butyl, cyclobutyl carbonyl; 2,2-difluoro propionyl, cyclopentylcarbonyl; tetrahydrochysene-2H-pyrans-4-base carbonyl, cyclopropyl carbonyl, propyl group carbonyl; N-ethylamino carbonyl, N-sec.-propyl aminocarboxyl, cyclopropyl alkylsulfonyl and ethylsulfonyl.
An embodiment more of the present invention provides formula I compound, wherein
R 1Be selected from
Figure BSA00000321451200114
R 2Be selected from-H, methyl, ethyl, the 1-propyl group, the 2-propyl group, the 1-butyl, the 2-butyl, the tertiary butyl, allyl group ,-S (=O) 2-CH 3,-S (=O) 2-CH 2CH 3, 2-methoxy ethyl, tetrahydropyran-4-base-methyl, 1-sulfonyl propyl base, cyclopropyl alkylsulfonyl, phenyl, benzenesulfonyl, 2-(methoxycarbonyl)-benzenesulfonyl; 2-(hydroxycarbonyl group)-benzenesulfonyl, 1-methyl isophthalic acid H-imidazol-4 yl-alkylsulfonyl, 1H-imidazoles-1-base-alkylsulfonyl, (the 5-methyl is different
Figure BSA00000321451200115
Azoles-4-yl) alkylsulfonyl, morpholine-4-base carbonyl, 4-amino-phenyl ,-CH 2-C (=O)-N (CH 3) 2,-C (=O)-N (CH 3) 2,-S (=O) 2-N (CH 3) 2,-S (=O) 2-NHCH 2CH 3,-C (=O)-CH 2CH 2CH 3,-CH 2-C (=O)-OCH 3,-CH 2-C (=O)-OCH 2CH 3,-CH 2-CO 2H, benzyl, 4-aminobenzyl; the 4-nitrobenzyl, 4-methyl sulphonyl-benzyl, 4-methylthio group-benzyl; 4-acetylaminohydroxyphenylarsonic acid benzyl, 4-methoxyl group-benzyl, 4-oxyethyl group-benzyl; 2,6-difluorobenzyl, (6-chloro-1; 3-benzodioxole-5-yl) methyl, (5-ethoxy carbonyl)-furans-2-base-methyl, (2-methyl isophthalic acid; 3-thiazole-4-yl)-and methyl, (5-methyl-different Azoles-4-yl)-and methyl, pyridine-2-ylmethyl, cyclobutylmethyl and cyclopropyl methyl; And
R 3Be selected from ethyl, sec.-propyl, propyl group; 2-methyl-propyl group, 1-butyl, 1-amyl group; 1-ethanoyl-piperidin-4-yl, tetramethylene sulfide-3-base, cyclopropyl methyl; cyclobutylmethyl, cyclopentyl-methyl, cyclobutyl; cyclopentyl, cyclohexyl, 4-tetrahydrochysene-2H-pyranyl; tetrahydrochysene-thiapyran-4-base, 1-imino-ethyl, 3; 4,5,6-tetrahydropyridine-2-base; 3,4-dihydro-2 h-pyrrole-5-base, tetrahydrofuran (THF)-3-ylmethyl; tetrahydrofuran (THF)-2-base, 1-methyl-4-piperidyl, 2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl; tetrahydrochysene-2H-pyrans-4-ylmethyl, 3,3; the 3-trifluoro propyl, 2,2-two fluoro ethyls; 2-hydroxycyclopent base, 3-methyl butyl, hexamethylene-3-alkene-1-ylmethyl and 2-ethyl-butyl.
In another embodiment, R 3Be selected from ethyl, sec.-propyl, propyl group, 2-methyl-propyl group; the 1-butyl, 1-amyl group, 1-ethanoyl-piperidin-4-yl; tetramethylene sulfide-3-base, cyclopropyl methyl, cyclobutylmethyl; cyclopentyl-methyl, cyclobutyl, cyclopentyl; cyclohexyl, 4-tetrahydrochysene-2H-pyranyl, tetrahydrochysene-thiapyran-4-base; 1-imino-ethyl, 3,4; 5,6-tetrahydropyridine-2-base, 3; 4-dihydro-2 h-pyrrole-5-base, tetrahydrofuran (THF)-3-ylmethyl, tetrahydrofuran (THF)-2-base; tetrahydrofuran (THF)-3-base, 1-methyl-4-piperidyl, 2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl; tetrahydrochysene-2H-pyrans-4-ylmethyl, 3,3; the 3-trifluoro propyl, 2,2-two fluoro ethyls; 2-hydroxycyclopent base, 3-methyl butyl, hexamethylene-3-alkene-1-ylmethyl and 2-ethyl-butyl.
Should be appreciated that when compound of the present invention contained one or more chiral centre, compound of the present invention can exist or is separated into mapping or diastereomeric form formula with mapping or diastereomeric form formula, perhaps exists as racemic mixture.The present invention includes any possible enantiomer, diastereomer, racemoid or its mixture of formula I compound.The optical activity form of The compounds of this invention can prepare in the following way: for example the chiral chromatography of racemoid separates, synthesizes from the optical activity raw material, perhaps based on following described asymmetric synthesis.
Be further appreciated that some compound of the present invention can be used as geometrical isomer, for example the E of alkene and Z isomer and exist.The present invention includes any geometrical isomer of formula I compound.It is also understood that the present invention comprises the tautomer of formula I compound.
It is also understood that some compound of the present invention can be with solvation, for example hydrated form exists, and the form of solvation does not exist.It is also understood that the present invention comprises all these solvation forms of formula I compound.
The salt of formula I compound also within the scope of the invention.The pharmacy acceptable salt of The compounds of this invention can use standard operation known in the art to obtain usually, for example the compound (for example alkylamine) by making enough alkalescence and suitable acid are (for example, HCl or acetate) reaction, obtain the acceptable negatively charged ion of physiology.Also can be by in water-bearing media, handle The compounds of this invention with the oxyhydroxide of monovalent basic metal or alkaline-earth metal or alkoxide (for example b-oxide or methoxide) or suitable alkaline organic amine (for example choline or meglumine), then handle to prepare corresponding alkali metal (for example sodium, potassium or lithium) salt or alkaline-earth metal (for example calcium) salt by conventional purification technique with suitable acid proton (for example carboxylic acid or phenol).
In one embodiment, above-mentioned formula I compound can be converted into pharmacy acceptable salt or its solvate, particularly acid salt for example hydrochloride, hydrobromate, phosphoric acid salt, acetate, formate, maleate, tartrate, Citrate trianion, mesylate or tosilate.
Now, we have found that The compounds of this invention has the activity as medicine, particularly as CB 1The conditioning agent of acceptor or part be agonist, partial agonist, inverse agonist or antagonist for example.More specifically, The compounds of this invention demonstrates as CB 1The selective active of receptor stimulant also is used for the treatment of, particularly alleviate various antalgesics, for example chronic pain (chronic pain), neuropathic pain (neuropathicpain), acute pain (acute pain), cancer pain (cancer pain), the pain that causes by rheumatoid arthritis, migraine (migraine), Encelialgia (visceral pain) etc.Yet this enumerating should not be construed as exhaustive.In addition, The compounds of this invention can be used for wherein existing or involving CB 1Other morbid state of function of receptors disorder.In addition, compound of the present invention can be used for treating cancer, multiple sclerosis, Parkinson's disease, Huntington Chorea, Alzheimer, anxiety disorder, obesity, gastrointestinal tract disease and cardiovascular disorder.Even compound of the present invention can be used for strengthening smoking and gives up (smoking cessation)
Compound of the present invention can be used as immunomodulator, and especially for autoimmune disease, for example sacroiliitis is used for dermatoplasty, organ transplantation and similar operation needs, is used for collagen disease, various transformation reactions, is used as antitumour drug and antiviral drug.
Compound of the present invention can be used for following morbid state, wherein has or involve the degeneration or the dysfunction of Cannabined receptor in example.This can be included in the isotopic labeling variant that uses The compounds of this invention in diagnostic techniques and the imaging applications (for example positron emission tomography (PET)).
Compound of the present invention is used for the treatment of diarrhoea; depressed; anxiety and illness (stress-related disorders) that stress be relevant; posttraumatic stress disorder (post-traumatic stress disorder) for example; panic disorder (panic disorder); generalized anxiety disorder; social phobia (social phobia) and obsessive compulsive disorder (obsessive compulsive disorder); the urinary incontinence (urinary incontinence); premature ejaculation; various mental illnesss; cough; pulmonary edema; (for example constipation of various gastrointestinal tract disease; functional gastrointestinal disease is irritable bowel syndrome (Irritable Bowel Syndrome) and functional dyspepsia for example); Parkinson's disease and other dyskinesia; traumatic brain injury; apoplexy; Cardioprotective after the myocardial infarction (cardioprotection); fat; vertebra hurt and dopy; comprise treatment alcohol; Nicotine; opioid and other drug abuse and sympathetic nervous system disorder be hypertension for example.
Compound of the present invention can be used as pain killer, uses in general anesthesia and supervision anesthetic care (monitoredanaesthesia care) process.The different properties combination of agents is generally used for keeping the balance of the required effect of narcosis (for example: forget, analgesia, loosening all muscles and calmness).This combination comprises suction narcotic, soporific, anxiolytic, neuromuscular blocking agent (neuromuscular blockers) and opioid.
Above-mentioned any formula I compound preparation be used for the treatment of in the medicine of above-mentioned any illness purposes also within the scope of the invention.
Another aspect of the present invention is the method that treatment suffers from the patient of above-mentioned any illness, wherein the above-mentioned formula I compound administration of significant quantity is extremely needed the patient of this treatment.
Therefore, the invention provides above-mentioned formula I compound or pharmacy acceptable salt or its solvate that is used for the treatment of.
On the other hand, the invention provides above-mentioned formula I compound or pharmacy acceptable salt or the purposes of its solvate in the medicine that preparation is used for the treatment of.
Unless opposite explanation is arranged in addition, in the context of the present specification, term " treatment " also comprises " prevention ".Term " treatment " and " remedially " also should correspondingly be understood.In the context of the present invention, term " treatment " also comprises the The compounds of this invention of effective dosage, to alleviate acute or chronic disease situation or the recurrence illness that is pre-existing in.This definition also comprises the prophylactic treatment and the continued treatment that is used for chronic disease that is used to prevent to recur illness.
Compound of the present invention can be used for treatment, especially for the various antalgesics of treatment, includes but not limited to: acute pain, chronic pain, neuropathic pain, backache, cancer pain and Encelialgia.
Treating for example man-hour of warm-blooded animal, compound of the present invention can be with the form of conventional medicine composition by the administration of various paths, comprise oral, intramuscular, subcutaneous, partly, in the nose, in the intraperitoneal, intrathoracic (intrathoracially), intravenously, epidural, sheath, through skin, chest indoor (intracerebroventricularly) and injection joint.
In an embodiment of the invention, route of administration can be oral, intravenously or intramuscular.
When determining for optimal each drug regimen of particular patient and dosage level, dosage will depend on the other factors that administration path, severity of disease, patient's age and body weight and attending doctor consider usually.
For from compound pharmaceutical composition of the present invention, inertia, pharmaceutically acceptable carrier can be solid or liquid.But the preparation of solid form comprises pulvis, tablet dispersible granule, capsule, cachet and suppository.
Solid carrier can be one or more materials, and it can be used as thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent or sheet disintegrating agent (table disintegrating agents); It also can be an encapsulating material.
In pulvis, carrier is fine comminuted solids, its can for the compound of the fine pulverizing of the present invention or the mixture of active ingredient.In tablet, active ingredient is compressed with suitable mixed and with required shape and size with the carrier with necessary bond property.
In order to prepare suppository composition, at first melt low melt wax (for example mixture of glycerin fatty acid ester and theobroma oil), then for example by stirring dispersed activity component within it.Pour into the uniform mixture of fusing in the mould of appropriate size then and make it cooling and solidify.
Suitable carriers can be magnesiumcarbonate, Magnesium Stearate, talcum, lactose, sugar, pectin, dextrin, starch, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.
Term " composition " also is intended to comprise active ingredient and the preparation that capsular encapsulating material is provided as carrier, and wherein active ingredient (being with or without other carrier) is by bonded carrier encirclement with it.Similarly, also comprise cachet.
Tablet, pulvis, cachet and capsule can be as being fit to oral solid dosage.
The composition of liquid form comprises solution, suspensoid and emulsion.For example, the sterilized water of active ingredient or water propylene glycol solution can be for being fit to the liquid preparation of administered parenterally.Liquid composition also can be formulated as the form of the polyoxyethylene glycol aqueous solution.
The aqueous solution for oral use can prepare by solubilization of active ingredient is also added suitable tinting material, seasonings, solubilizing agent and thickening material as required in water.Aqueous suspensions for oral use can prepare for example natural synthetical glue of described cohesive material, resin, methylcellulose gum, Xylo-Mucine and known other suspension agent of medicine formulation art by the active ingredient of fine pulverizing and cohesive material are dispersed in the water.
Based on the mode of administration, pharmaceutical composition preferably includes 0.05% to 99w% (weight %), more preferably 0.10 to 50w% The compounds of this invention, and all per-cents all are based on the composition gross weight.
Those of ordinary skills can utilize known standard to determine to put into practice treatment significant quantity of the present invention, and described standard comprises age, body weight and the reaction of single patient, and can explain in the scope of the disease of being treated or preventing.
Scope of the present invention also comprises the purposes of any formula I compound in the preparation medicine of above-mentioned definition.
Any formula I compound that scope of the present invention also comprises above-mentioned definition is used for the treatment of purposes in the medicine of pain in preparation.
In addition, provide any formula I compound to be used for the treatment of purposes in the medicine of various antalgesics in preparation, pain includes but not limited to: acute pain, chronic pain, neuropathic pain, backache, cancer pain and Encelialgia.
Another aspect of the present invention provides the method for the treatment of the patient who suffers from above-mentioned any illness, wherein the above-mentioned formula I compound administration of significant quantity is extremely needed the patient of this treatment.
In addition, provide a kind of pharmaceutical composition, comprise formula I compound or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
Particularly, be provided for treatment, more specifically be used for the treatment of the pharmaceutical composition of pain, it comprises formula I compound or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
In addition, be provided for treating the pharmaceutical composition of above-mentioned any illness, it comprises formula I compound or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
On the other hand, the invention provides the method for preparing The compounds of this invention.
In one embodiment, the invention provides the preparation method of formula II compound, comprising:
Figure BSA00000321451200161
Make formula III compound and formula R 11The compound reaction of-CHO,
Figure BSA00000321451200162
Wherein
R 1And R 2Definition the same; And
R 11Be selected from C 3-6Heterocyclylalkyl, C 3-6Cycloalkyl and C 1-6Alkyl wherein defines R 11The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Cycloalkyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen.
Randomly, formula II compound and formula R 11The step of the compound reaction of-CHO is carried out in the presence of reductive agent such as sodium triacetoxy borohydride, sodium cyanoborohydride or sodium borohydride.
In another embodiment, the invention provides the preparation method of formula IV compound, comprising:
Figure BSA00000321451200163
Make formula III compound and formula
Figure BSA00000321451200171
Compound reaction,
Figure BSA00000321451200172
Wherein
R 1And R 2Definition the same; And
Figure BSA00000321451200173
Be selected from C 3-6Heterocyclylalkyl and C 3-6Cycloalkyl, wherein said C 3-6Heterocyclylalkyl and C 3-6Cycloalkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen.
Randomly, formula II compound and formula
Figure BSA00000321451200174
The step of compound reaction in the presence of reductive agent such as sodium triacetoxy borohydride, sodium cyanoborohydride or sodium borohydride, carry out.
In another embodiment, the invention provides the preparation method of formula V compound, comprising:
Figure BSA00000321451200175
Make formula VI compound and R 5-C (=O)-the Cl reaction,
Figure BSA00000321451200176
VI
R wherein 2, R 3And R 5Definition the same.
Randomly, formula VI compound and R 5-C (=O)-step of Cl reaction carries out in the presence of alkali such as triethylamine.
In another embodiment, the invention provides the preparation method of formula VII compound, comprising:
Figure BSA00000321451200181
Make formula VIII compound and R 8-SO 2-Cl reaction,
Figure BSA00000321451200182
R wherein 2, R 3, R 5And R 7Definition the same.
Randomly, formula VIII compound and R 8-SO 2The step of-Cl reaction is carried out in the presence of alkali such as triethylamine.
In another embodiment, the invention provides the preparation method of the compound of formula IX, comprising:
Figure BSA00000321451200183
Make formula VIII compound and R 10R 9N-SO 2-Cl reaction,
Figure BSA00000321451200191
R wherein 2, R 3, R 7, R 9And R 10Definition the same.
Randomly, formula VIII compound and R 10R 9N-SO 2The step of-Cl reaction is carried out in the presence of alkali such as triethylamine.
In another embodiment, the invention provides the preparation method of the compound of formula X, comprising:
Figure BSA00000321451200192
Make formula VI compound and R 6The NCO reaction,
Figure BSA00000321451200193
R wherein 2, R 3And R 6Definition the same.
Randomly, formula VI compound and R 6The step of NCO reaction is carried out in the presence of alkali such as triethylamine.
Compound of the present invention can also prepare according to the route of synthesis described in the scheme 1～10.
General approach 1: compound 1-114,116-130,133-139,149-152,192-200 and 219-221
Figure BSA00000321451200201
General approach 2: compound 115,131,132,201,202-203
Figure BSA00000321451200202
General approach 3: compound 140-148
Figure BSA00000321451200203
General approach 4: compound 153-175
Figure BSA00000321451200211
General approach 5: compound 176-178
General approach 6: compound 179-191 and 212-218
Figure BSA00000321451200221
General approach 7: compound 206-208
Figure BSA00000321451200222
General approach 8:204
Figure BSA00000321451200223
General approach 9:205
Figure BSA00000321451200231
General approach 10: compound 209-211
Figure BSA00000321451200232
The invention still further relates to following:
Item 1. formula I compounds or its pharmacy acceptable salt, diastereomer, enantiomer or its mixture:
Figure BSA00000321451200233
Wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8With-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl is optional to be selected from following group by one or more and to replace :-OR, R, NO 2,-CO 2H ,-CO 2-R;-SO 2-R; Halogen;-OH;-NH 2-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl;
R 4Be selected from nitrogenous C 3-9Heterocyclic radical and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclic radical can be chosen wantonly and is selected from following group by one or more and replace: C 1-6Alkyl, phenyl, C 1-6Alkoxyl group ,-NH 2,-OH, halo C 1-6Alkyl and halogen; And
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl.
Item 2. compounds according to item 1, wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8,-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from C 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, and oxyethyl group ,-S (=O) 2CH 3, methyl, ethyl ,-NO 2,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl and C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, and oxyethyl group ,-S (=O) 2CH 3, methyl, ethyl ,-NO 2,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 4Be selected from nitrogenous C 3-9Heterocyclylalkyl and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclylalkyl can be chosen wantonly and is selected from following group by one or more and replace: methyl, ethyl, phenyl, methoxyl group, oxyethyl group ,-OH, trifluoromethyl and halogen; And
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, phenyl, benzyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-methyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-methyl; Hydroxyl-C 1-6Alkyl, methoxyl group-C 1-6Alkyl and oxyethyl group-C 1-6Alkyl.
Item 3. compounds according to item 1, wherein
R 1Be selected from-C (=O)-R 4With-NH-C (=O)-R 5
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl, benzyl and C 3-5Heteroaryl-methyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl, benzyl and C 3-5Heteroaryl-methyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group ,-NO 2,-S (=O) 2CH 3, methyl, ethyl ,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-methyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-methyl and C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-methyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-methyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen;
R 4Be selected from piperidyl, piperazinyl and morpholinyl, wherein said piperidyl, piperazinyl and morpholinyl be optional to be selected from following group by one or more and to replace: methyl, ethyl, methoxyl group, oxyethyl group ,-OH, methylol, trifluoromethyl and halogen; And
R 9And R 10Be independently selected from :-H, C 1-6Alkyl and C 2-6Thiazolinyl.
Item 4. compounds according to item 1, wherein
R 1Be selected from
Figure BSA00000321451200251
Figure BSA00000321451200261
Figure BSA00000321451200271
R 2Be selected from methyl, ethyl, the 1-propyl group, the 2-propyl group, the 1-butyl, the 2-butyl, the tertiary butyl, allyl group ,-S (=O) 2-CH 3,-S (=O) 2-CH 2CH 3, 2-methoxy ethyl, tetrahydropyran-4-base-methyl, 1-sulfonyl propyl base, cyclopropyl alkylsulfonyl, phenyl, benzenesulfonyl, 2-(methoxycarbonyl)-benzenesulfonyl; 2-(hydroxycarbonyl group)-benzenesulfonyl, 1-methyl isophthalic acid H-imidazol-4 yl-alkylsulfonyl, 1H-imidazoles-1-base-alkylsulfonyl, (the 5-methyl is different
Figure BSA00000321451200272
Azoles-4-yl) alkylsulfonyl, morpholine-4-base carbonyl, 4-amino-phenyl,
-CH 2-C (=O)-N (CH 3) 2,-C (=O)-N (CH 3) 2,-S (=O) 2-N (CH 3) 2,-S (=O) 2-NHCH 2CH 3,-C (=O)-CH 2CH 2CH 3,-CH 2-C (=O)-OCH 3,-CH 2-C (=O)-OCH 2CH 3,-CH 2-CO 2H, benzyl, 4-aminobenzyl; the 4-nitrobenzyl, 4-methyl sulphonyl-benzyl, 4-methylthio group-benzyl; 4-acetylaminohydroxyphenylarsonic acid benzyl, 4-methoxyl group-benzyl, 4-oxyethyl group-benzyl; 2,6-difluorobenzyl, (6-chloro-1; 3-benzodioxole-5-yl) methyl, (5-ethoxy carbonyl)-furans-2-base-methyl, (2-methyl isophthalic acid; 3-thiazole-4-yl)-and methyl, (5-methyl-different
Figure BSA00000321451200281
Azoles-4-yl)-and methyl, pyridine-2-ylmethyl, cyclobutylmethyl and cyclopropyl methyl;
R 3Be selected from ethyl, sec.-propyl, propyl group, 2-methyl-propyl group; the 1-butyl, 1-amyl group, 1-ethanoyl-piperidin-4-yl, tetramethylene sulfide-3-base; the cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclobutyl; cyclopentyl, cyclohexyl, 4-tetrahydrochysene-2H-pyranyl, tetrahydrochysene-thiapyran-4-base; the 2-pyrimidyl, 1-imino-ethyl, 2-pyridyl, 3; 4,5,6-tetrahydropyridine-2-base; 3,4-dihydro-2 h-pyrrole-5-base, 2-pyridyl-methyl; the 3-pyridylmethyl, 4-pyridylmethyl, 1-methyl-4-piperidyl; the 4-piperidyl, (6-methyl-pyridine-2-yl) methyl, (2-ethyl-4-methyl isophthalic acid H-imidazoles-5-yl) methyl; tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, tetrahydrofuran (THF)-3-ylmethyl; 1-ethyl-1H-pyrazoles-4-base, 1,3-dimethyl-1H-pyrazoles-5-base; (3-picoline-4-yl) methyl, 1,3-
Figure BSA00000321451200282
Azoles-2-ylmethyl, 1,3-
Figure BSA00000321451200283
Azoles-5-ylmethyl, 2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl, tetrahydrochysene-2H-pyrans-4-ylmethyl, 2-phenylethyl, 2-methoxy-benzyl, 3,3,3-trifluoro propyl, 2,2-two fluoro ethyls, 2-hydroxycyclopent base, (1-ethyl-3-methyl isophthalic acid H-pyrazoles-5-yl) methyl, 2,1,3-benzo
Figure BSA00000321451200284
Diazole-5-ylmethyl, 3-thienyl methyl, 2-trifluoromethyl-benzyl; the 3-methyl butyl, hexamethylene-3-alkene-1-ylmethyl, 2-fluoro-6-methoxy-benzyl; 2-phenyl-propyl group, 2-ethyl-butyl, cyclobutyl carbonyl; 2,2-difluoro propionyl, cyclopentylcarbonyl; tetrahydrochysene-2H-pyrans-4-base carbonyl, cyclopropyl carbonyl, propyl group carbonyl; N-ethylamino carbonyl, N-sec.-propyl aminocarboxyl, cyclopropyl alkylsulfonyl and ethylsulfonyl.
Item 5. compounds according to item 1, wherein
R 1Be selected from
R 2Be selected from-H, methyl, ethyl, the 1-propyl group, the 2-propyl group, the 1-butyl, the 2-butyl, the tertiary butyl, allyl group ,-S (=O) 2-CH 3,-S (=O) 2-CH 2CH 3, 2-methoxy ethyl, tetrahydropyran-4-base-methyl, 1-sulfonyl propyl base, cyclopropyl alkylsulfonyl, phenyl, benzenesulfonyl, 2-(methoxycarbonyl)-benzenesulfonyl; 2-(hydroxycarbonyl group)-benzenesulfonyl, 1-methyl isophthalic acid H-imidazol-4 yl-alkylsulfonyl, 1H-imidazoles-1-base-alkylsulfonyl, (the 5-methyl is different Azoles-4-yl) alkylsulfonyl, morpholine-4-base carbonyl, 4-amino-phenyl,
-CH 2-C (=O)-N (CH 3) 2,-C (=O)-N (CH 3) 2,-S (=O) 2-N (CH 3) 2,-S (=O) 2-NHCH 2CH 3,-C (=O)-CH 2CH 2CH 3,-CH 2-C (=O)-OCH 3,-CH 2-C (=O)-OCH 2CH 3,-CH 2-CO 2H, benzyl, 4-aminobenzyl; the 4-nitrobenzyl, 4-methyl sulphonyl-benzyl, 4-methylthio group-benzyl; 4-acetylaminohydroxyphenylarsonic acid benzyl, 4-methoxyl group-benzyl, 4-oxyethyl group-benzyl; 2,6-difluorobenzyl, (6-chloro-1; 3-benzodioxole-5-yl) methyl, (5-ethoxy carbonyl)-furans-2-base-methyl, (2-methyl isophthalic acid; 3-thiazole-4-yl)-and methyl, (5-methyl-different
Figure BSA00000321451200291
Azoles-4-yl)-and methyl, pyridine-2-ylmethyl, cyclobutylmethyl and cyclopropyl methyl; And
R 3Be selected from ethyl, sec.-propyl, propyl group, 2-methyl-propyl group; the 1-butyl, 1-amyl group, 1-ethanoyl-piperidin-4-yl; tetramethylene sulfide-3-base, cyclopropyl methyl, cyclobutylmethyl; cyclopentyl-methyl, cyclobutyl, cyclopentyl; cyclohexyl, 4-tetrahydrochysene-2H-pyranyl, tetrahydrochysene-thiapyran-4-base; 1-imino-ethyl, 3,4; 5,6-tetrahydropyridine-2-base, 3; 4-dihydro-2 h-pyrrole-5-base, tetrahydrofuran (THF)-3-ylmethyl, tetrahydrofuran (THF)-2-base; tetrahydrofuran (THF)-3-base, 1-methyl-4-piperidyl, 2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl; tetrahydrochysene-2H-pyrans-4-ylmethyl, 3,3; the 3-trifluoro propyl, 2,2-two fluoro ethyls; 2-hydroxycyclopent base, 3-methyl butyl, hexamethylene-3-alkene-1-ylmethyl and 2-ethyl-butyl.
6. 1 kinds of compounds of item, it is selected from:
5-allyl group-2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(1-ethanoyl piperidin-4-yl)-5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-3-thienyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(cyclopentyl-methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-cyclohexyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-thiapyran-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-amyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridine-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[(6-picoline-2-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridin-3-yl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridin-4-yl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(2-ethyl-4-methyl isophthalic acid H-imidazoles-5-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(3-methyl butyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(hexamethylene-3-alkene-1-ylmethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2-fluoro-6-methoxy-benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(2-phenyl propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2-ethyl-butyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-butyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(1-ethyl-1H-pyrazoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(1,3-dimethyl-1H-pyrazoles-5-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[(3-picoline-4-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(1,3-
Figure BSA00000321451200311
Azoles-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(2-phenylethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2-methoxy-benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(1-ethyl-3-methyl isophthalic acid H-pyrazoles-5-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2,1, the 3-benzo
Figure BSA00000321451200312
Diazole-5-ylmethyl)-and 8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(1-ethyl-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3-thienyl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[2-(trifluoromethyl) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-piperidin-4-yl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2,2-difluoro propionyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(cyclopentylcarbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(cyclopropyl carbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-N-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] indoles-2-methane amide;
5-allyl group-N-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] indoles-2-methane amide;
5-allyl group-2-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridine-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[(6-picoline-2-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(1,3-
Figure BSA00000321451200321
Azoles-5-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(1,3- Azoles-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-ethyl-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopentyl-methyl)-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridin-3-yl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-2-(3-methyl butyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(hexamethylene-3-alkene-1-ylmethyl)-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-butyl-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridin-4-yl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-amyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(2-phenylethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(tetrahydrofuran (THF)-3-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(2,2-two fluoro ethyls)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
(1R*, 2R*)-2-{8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2-yl } cyclopentanol;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-pyridine-2-base-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(3,4,5,6-tetrahydropyridine-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(3,4-dihydro-2 h-pyrrole-5-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclobutyl carbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopentylcarbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(2,2-difluoro propionyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-2-isobutyl--8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclobutyl-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclobutyl carbonyl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-pyrimidine-2-base-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3,4,5,6-tetrahydropyridine-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
1-{5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2-yl } ethyliminum;
2-(3,4-dihydro-2 h-pyrrole-5-yl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(3,4-dihydro-2 h-pyrrole-5-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclobutyl-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(2,2-two fluoro ethyls)-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(sec.-propyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3,3, the 3-trifluoro propyl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
2-cyclopentyl-N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
2-cyclobutyl-N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide;
2-cyclobutyl-N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide;
5-butyryl radicals-2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(cyclobutylmethyl)-2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-[(5-methyl is different
Figure BSA00000321451200371
Azoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-the 5-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-{2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide;
2-{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide;
2-{2-cyclohexyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide;
2-cyclobutyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } acetate;
2-cyclohexyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate;
5-(2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl)-the 2-methylfuroate;
5-(2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl)-the 2-furancarboxylic acid;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles 2-oxide compound;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methyl sulphonyl) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
4-[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] phenyl } amine;
N-{4-[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] phenyl } ethanamide;
4-{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } phenyl) amine;
2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-benzyl-2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-sec.-propyl-5-(4-methoxy-benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-amyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-[(6-chloro-1,3-benzodioxole-5-yl) methyl]-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2, the 6-difluorobenzyl)-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-oxyethyl group piperidines-1-yl) carbonyl]-2-sec.-propyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(cyclobutyl)-8-[(3-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
1-{[5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidines-4-methane amide;
1-{[5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidines-4-alcohol;
(1-{[5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidin-4-yl) methyl alcohol;
5-methyl-8-[(4-methylpiperazine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-8-(morpholine-4-base carbonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-8-(piperidines-1-base carbonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-(1,4-two oxa-s-8-azaspiro [4.5] decane-8-base carbonyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
N-(1,1-titanium dioxide tetrahydrochysene-3-thienyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
N-[2-(dimethylamino)-2-oxoethyl]-N, 5-dimethyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
N-(2-hydroxyethyl)-N, 5-dimethyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-N-(2-morpholine-4-base ethyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-N, 2-two (tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-N-(pyridin-4-yl methyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
N-(2-methoxy ethyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-N-(tetrahydrofuran (THF)-2-ylmethyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
N-ethyl-5-methyl-N-(pyridin-4-yl methyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-N-phenyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-8-{[4-(trifluoromethyl) piperidines-1-yl] carbonyl }-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-tertiary butyl piperidines-1-yl) carbonyl]-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4,4-lupetidine-1-yl) carbonyl]-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-8-[(4-Phenylpiperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
N-(5-allyl group-2-cyclopentyl-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N-methyl benzenesulfonamide;
N-methyl-N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] benzsulfamide;
N-[5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] benzsulfamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) benzsulfamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopropane sulphonamide;
N '-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N, N-dimethyl methyl acid amides;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) ethyl sulfonamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) benzamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) propionic acid amide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopropane carboxamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopentane formamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N '-ethyl carbamide;
N-cyclopentyl-N '-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) urea;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N '-phenylurea;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(benzenesulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } methyl benzoate;
2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } phenylformic acid;
2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } the methyl benzoate tfa salt;
2-cyclobutyl-5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(ethylsulfonyl)-2-(tetrahydrofuran (THF)-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-2-(1-methyl piperidine-4-yl)-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(morpholine-4-base carbonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
The 5-[(5-methyl is different
Figure BSA00000321451200421
Azoles-4-yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
N-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
5-(ethylsulfonyl)-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
(1-{[2-cyclobutyl-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidin-4-yl) methyl alcohol;
1-{[2-cyclobutyl-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidines-4-alcohol;
N-[5-(methyl sulphonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] cyclopentane formamide;
N-[5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] tetramethyleneimine-1-methane amide;
N-[5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide;
(trans-4-{[(2-cyclopentyl-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) amino] carbonyl } cyclohexyl) t-butyl carbamate;
Trans-N-(2-cyclopentyl-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl)-4-[(2,2-dimethyl propylene acyl group) amino] cyclohexane carboxamide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] cyclohexane carboxamide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] tetrahydrochysene-2H-pyrans-4-methane amide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] cyclopentane formamide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] tetrahydrofuran (THF)-2-methane amide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] the tetramethylene methane amide;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(pyridine-2-ylmethyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(ethylsulfonyl)-2-(1-methyl piperidine-4-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
And pharmacy acceptable salt.
7. according to each compound in the item 1～6, and it is as medicine.
8. are used for the treatment of purposes in the medicine of pain according to each compound in the item 1～6 in preparation.
9. are used for the treatment of purposes in the medicine of anxiety disorder according to each compound in the item 1～6 in preparation.
10. are used for the treatment of cancer in preparation, multiple sclerosis, Parkinson disease, Huntington Chorea, Alzheimer disease, the purposes in the medicine of disorder of gastrointestinal tract and cardiovascular disorder according to each compound in the item 1～6.
11. 1 kinds of pharmaceutical compositions, it comprises according to each compound and pharmaceutically acceptable carrier in the item 1～6.
12. 1 kinds of methods for the treatment of warm-blooded animal pain, comprise with the treatment significant quantity according to each compound administration in the item 1～6 in the animal of this treatment of needs.
The method of 13. 1 kinds of preparation formula II compounds of item comprises:
II
Make formula III compound and formula R 11The compound reaction of-CHO,
Figure BSA00000321451200441
Wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8,-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl;
R 4Be selected from nitrogenous C 3-9Heterocyclic radical and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclic radical can be chosen wantonly and is selected from following group by one or more and replace: C 1-6Alkyl, phenyl, C 1-6Alkoxyl group ,-NH 2,-OH, halo C 1-6Alkyl and halogen;
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl; And
R 11Be selected from C 3-6Heterocyclylalkyl, C 3-6Cycloalkyl and C 1-6Alkyl wherein defines R 11The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Cycloalkyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen.
The method of 14. 1 kinds of preparation formula IV compounds of item comprises:
Figure BSA00000321451200451
Make formula III compound and formula Compound reaction,
Figure BSA00000321451200453
Wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8,-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl;
R 4Be selected from nitrogenous C 3-9Heterocyclic radical and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclic radical can be chosen wantonly and is selected from following group by one or more and replace: C 1-6Alkyl, phenyl, C 1-6Alkoxyl group ,-NH 2,-OH, halo C 1-6Alkyl and halogen;
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl; And
Be selected from C 3-6Heterocyclylalkyl and C 3-6Cycloalkyl, wherein said C 3-6Heterocyclylalkyl and C 3-6Cycloalkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen.
The method of 15. 1 kinds of preparation formula V compounds of item comprises:
Figure BSA00000321451200462
Make formula VI compound and R 5-C (=O)-the Cl reaction,
Figure BSA00000321451200463
Wherein
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl is optional to be selected from following group by one or more and to replace :-OR, R, NO 2,-CO 2H ,-CO 2-R;-SO 2-R; Halogen;-OH;-NH 2-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl; And
R 5, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl.
The method of item 16-preparation formula VII compound comprises:
Figure BSA00000321451200471
Make formula VIII compound and R 8-SO 2-Cl reaction,
Figure BSA00000321451200472
Wherein
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl is optional to be selected from following group by one or more and to replace :-OR, R, NO 2,-CO 2H ,-CO 2-R;-SO 2-R; Halogen;-OH;-NH 2-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl; And
R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl.
The method of the compound of 17. 1 kinds of preparation formula IX of item comprises:
Figure BSA00000321451200481
Make formula VIII compound and R 10R 9N-SO 2-Cl reaction,
Figure BSA00000321451200482
Wherein
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl is optional to be selected from following group by one or more and to replace :-OR, R, NO 2,-CO 2H ,-CO 2-R;-SO 2-R; Halogen;-OH;-NH 2-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl; And
R 7, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl.
The method of the compound of 18. 1 kinds of preparation formula X of item comprises:
Make formula VI compound and R 6The NCO reaction,
Figure BSA00000321451200492
Wherein
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl is optional to be selected from following group by one or more and to replace :-OR, R, NO 2,-CO 2H ,-CO 2-R;-SO 2-R; Halogen;-OH;-NH 2-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl; And
R 6, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl.
Biological assessment
HCB 1 And hCB 2 Receptors bind
The human CB of Receptor Biology will be derived from 1Acceptor (hCB 1) or derive from the human CB of BioSignal 2Acceptor (hCB 2) film thaws at 37 ℃, passes 25-number blunt nosed pin 3 times, at cannaboid binding buffer liquid (50mM Tris, 2.5mM EDTA, 5mM MgCl 2With 0.5mg/mL BSA, fatty acids not, pH7.4) in dilution, and will contain an amount of proteinic aliquots containig and be dispensed in the 96-orifice plate.Estimate The compounds of this invention to hCB from 10 dose points-response curve 1And hCB 2IC 50, described dose-response curve is with every hole 20000-25000dpm's in the final volume of 300 μ l 3H-CP55,940 (0.17-0.21nM) and obtain.Total binding and non-specific binding when determining not contain and contain 0.2 μ M HU210 respectively.With the plate vortex and incubated at room temperature 60 minutes, filter by Unifilters GF/B (preimpregnation in 0.1% polymine), collect with Tomtec or Packard collector, and use 3mL lavation buffer solution (50mM Tris, 5mM MgCl 2, 0.5mg BSA, pH 7.0) washing.With filter 55 ℃ of dryings 1 hour.Add the MS-20 scintillation solution, every hole 65 μ l calculate radioactivity (cpm) then in TopCount (Packard).
HCB 1 And hCB 2 GTP γ S combination
The human CB of Receptor Biology will be derived from 1Acceptor (hCB 1) or human CB 2Acceptor (hCB 2) film (BioSignal) thaws at 37 ℃, passes 25-number blunt nosed pin 3 times, at GTP γ S binding buffer liquid (50mM Hepes, 20mM NaOH, 100mM NaCl, 1mM EDTA, 5mM MgCl 2, 0.1%BSA, pH 7.4) in the dilution.The EC of The compounds of this invention 50And E MaxEstimated by 10 dose points-response curve, described dose-response curve is to contain an amount of membranin and GTPg with every hole in 300 μ l volumes 35(0.11-0.14nM 100000-130000dpm) obtains S.Determine not contain and contain 1 μ M (hCB respectively 2) or 10 μ M (hCB 1) Win 55, the fundamental sum maximal stimulation combination of 212-2.With film with 56.25 μ M (hCB 2) or 112.5 μ M (hCB 1) GDP cultivated 5 minutes in advance, was dispensed to plate (final 15 μ M (hCB then 2) or 30 μ M (hCB 1) GDP).Cultivated 60 minutes with the plate vortex and in room temperature, filter, collect, and use 3mL lavation buffer solution (50mM Tris, 5mM MgCl with Tomtec or Packard collector by Unifilters GF/B (preimpregnation in water) 2, 50mM NaCl, pH 7.0) washing.With filter 55 ℃ of dryings 1 hour.Add the MS-20 scintillation solution, every hole 65 μ l calculate radioactivity (cpm) then in TopCount (Packard).Carry out antagonist in the same way and reverse (antagonist reversal) research, difference is: (a) obtain the agonist dose-response curve in the presence of the antagonist of constant density, or (b) obtain the antagonist dose-response curve in the presence of the agonist of constant density.
Based on above-mentioned test, particular compound of the present invention can use following formula to measure to the dissociation constant (Ki) of concrete acceptor:
Ki＝IC 50/(1+[rad]/Kd)，
IC wherein 50Be the concentration that The compounds of this invention was observed for 50% when displacement;
[rad] is the standard or the reference concentration of radioligand this moment; With
Kd is the dissociation constant of radioligand to concrete acceptor.
Said determination finds that compound of the present invention is to human CB 1Acceptor has activity.
Embodiment
Now be described more specifically the present invention by the following examples, described embodiment has described the method for preparation, purifying, analysis and biological test compound of the present invention, and to should not be construed as be limitation of the present invention.
Embodiment 1.5-allyl group-2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Steps A: 2-(tert-butoxycarbonyl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid
Figure BSA00000321451200522
(18.6g, 98.6mmol) (17.0g is 110mmol) two with 4-piperidone monohydrate hydrochloride with 4-hydrazino-benzoic acid hydrochloride
Figure BSA00000321451200523
Reflux is spent the night in alkane (300ml) and the concentrated hydrochloric acid (30ml), makes it to be cooled to room temperature, collecting precipitation, and vacuum concentrated filtrate is to doing, and resistates water (50mL) is handled, solid collected by filtration.Combining solid does not have purifying just to use.
Above-mentioned solid intermediate is dissolved in methyl alcohol (250mL), adjust pH to about 9-10 with 5N NaOH, add tert-Butyl dicarbonate (di-tert-butyl the dicarbonate) (13.0g that contracts, 59.6mmol) and with reactant stirring 2 hours, then pH is adjusted to about 9-10, add one contract tert-Butyl dicarbonate (5.0g, 22.9mmol), and with reactant in stirred overnight at room temperature.With 2N NaOH pH is adjusted to about 9-10 once more, and adds one of 3g once more and contract that (3.0g 13.7mmol), and stirred reactant 2 hours tert-Butyl dicarbonate once more.Vacuum concentration MeOH, resistates water (100mL) dilution, (2 * 200mL) extractions, water is acidified with acetic acid to pH～5 by means of stirring with methylene dichloride.Collect white solid and dry (15.2g, 48.7% in two steps).
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Product (the 2-(tert-butoxycarbonyl)-2 of steps A will be derived from, 3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid, 4.80g, 15.2mmol) be dissolved in DMF (80mL), add 4-methyl piperidine (2mL successively, 16.9mmol), diisopropyl ethyl amine (7.0mL, 38.9mmol) and HATU (7.60g, 20.0mmol).This mixture stirring at room 1 hour, and will be reacted water (5mL) cancellation.Solvent removed in vacuo obtains faint yellow solid, this solid water (100mL) is handled and collected by filtering, recrystallization obtains required product (4.60g) in methyl alcohol then, with the filtrate vacuum concentration, and in the last purifying of silica gel (0-40%EtOAc/ methylene dichloride), obtain the other required product of 1.10g, the yield of merging is 94.5%.MS：398.1(M+1)。
Step C:5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Under 0 ℃ and nitrogen atmosphere, with 60%NaH (480mg 12.0mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (2.42g is 6.08mmol) in the suspension in DMF (50mL) for the Indoline-2-carboxylic acid tert-butyl ester.With this mixture stirring at room 30 minutes, then room temperature add allyl bromide 98 (1.0mL, 11.6mmol), and with reaction mixture stirring at room 1 hour.Solvent removed in vacuo also is dissolved in methylene dichloride (150mL) with resistates, and dried over sodium sulfate is used in water (50mL) washing.Removing desolvates obtains crude product, and it through silica gel (0-30%EtOAc/ methylene dichloride) purifying, is obtained required product (2.48g, 93.5%).MS：438.1(M+1)。
Step D:5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200541
At 0 ℃, with 5-allyl group-8-[(4-methyl piperidine-1-yl of method A (HCl salt)) carbonyl]-1,3,4, (315mg 0.720mmol) adds in the ethyl acetate solution (15mL) of saturated HCl 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes at 0 ℃, and removes and desolvate, obtain required product 5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the hydrochloride form (235mg, 87%) of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.MS(M+1)：338.0。
5-allyl group-8-[(4-methyl piperidine-1-yl with method B (tfa salt)) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (2.45g 5.60mmol) is dissolved in methylene dichloride (50mL) and add trifluoroacetic acid (10mL) in reaction mixture to the Indoline-2-carboxylic acid tert-butyl ester.With this mixture stirring at room 1 hour.Vacuum is removed excessive trifluoroacetic acid, obtains thick 5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the trifluoroacetic acid salt form (2.70g) of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.
Step e: carbonyl 5-allyl group-2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl)]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200542
With sodium triacetoxy borohydride (100mg, 0.474mmol) add to 5-allyl group-8-[(4-methyl piperidine-1-yl of the method A that derives from step D) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (101mg is 0.271mmol) and in methylene dichloride (3mL) mixture of cyclopanecarboxaldehyde (50 μ L) for indoles HCl salt.This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Solution (5mL) washing, and use Na 2SO 4Dry.Again be dissolved in ether (10mL) with this dichloromethane solution vacuum concentration and with resistates, under agitation drip the HCl/ diethyl ether solution of 1N.Collect solid and dry, obtain required product 5-allyl group-2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the HCl salt (107mg, 93%) of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.MS(M+1)：392.0； 1H?NMR(400MHz，CD 3OD)δppm?0.39-0.62(m，2H)，0.68-0.91(m，2H)，0.99(d，J＝6.44Hz，3H)，1.07-1.43(m，3H)，1.48-1.97(m，3H)，2.81-3.36(m，6H)，3.52-3.66(m，1H)，3.70-3.92(m，1H)，3.93-4.15(m，1H)，4.44(d，J＝14.25Hz，1H)，4.51-4.70(m，1H)，4.75-4.88(m，4H)，5.14(dd，J＝10.35，1.17Hz，1H)，5.81-6.16(m，1H)，7.13-7.34(m，1H)，7.49(d，J＝8.40Hz，1H)，7.65(d，J＝1.17Hz，1H)。
Embodiment 2.5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200551
According to the general method described in embodiment 1 step e, by tetrahydrochysene-4H-pyrans-4-ketone (30mg), 5-allyl group-8-[(4-methyl piperidine-1-yl by preparation among the embodiment 1 step D (method B)) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salts (50mg), the preparation title compound.MS(M+1)：422.1。 1H?NMR(600MHz，CD 3OD)δppm?1.01(d，J＝6.14Hz，3H)，1.08-1.32(m，2H)，1.55-1.88(m，3H)，1.87-2.01(m，2H)，2.20(s，2H)，2.88(s，1H)，3.06-3.18(m，1H)，3.19-3.28(m，2H)，3.52(t，J＝11.78Hz，2H)，3.55-3.64(m，1H)，3.67-3.77(m，1H)，3.77-3.89(m，1H)，4.05(d，J＝10.24Hz，1H)，4.10-4.19(m，2H)，4.54(d，J＝13.31Hz，1H)，4.59-4.67(m，1H)，4.76(d，J＝13.31Hz，1H)，4.81-4.88(m，2H)，4.91-4.93(m，1H)，5.17(d，J＝10.24Hz，1H)，5.94-6.07(m，1H)，7.27(d，J＝8.19Hz，1H)，7.48(d，J＝8.19Hz，1H)，7.63(s，1H)。C 26H 35N 3O 22C 2HF 3O 2The analytical calculation value: C, 55.46; H, 5.74; N, 6.47.Measured value: C, 55.67; H, 5.59; N, 6.34.
Embodiment 3-10 presses and method identical described in the embodiment 2 preparation.
Table 1
Figure BSA00000321451200552
Figure BSA00000321451200561
Figure BSA00000321451200571
Embodiment 11-36: general method
Compound among the embodiment 11-36 prepares with plate form (plate format): utilize Tecan, with 5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] the methylene dichloride (～0.16M of indoles tfa salt, 0.5mL, 80umol) solution/hole and corresponding aldehyde (～0.5M, 0.25mL, 125umol)/hole is assigned in the plate, and utilizes solid dispenser with NaBH (OAc) 3(～30mg)/hole is assigned in the plate hole.With the plate shaken over night, add 1N NaOH (0.5mL)/hole, plate is shaken 2 minutes then, organic phase is transferred in the new plate, water extracts with methylene dichloride (0.5mL)/hole, by means of process Hydromatrix (a kind of diatomite) (～0.5g/ hole), with the organic solution drying of the merging in each hole.Remove solution by Genevac vaporizer vacuum.Plate is carried out purifying by preparation type LCMS, and by analyzing LCMS (10-95%CH 3CN, 3 minutes) obtain the purity of compound.
Table 2
Figure BSA00000321451200581
Figure BSA00000321451200591
Figure BSA00000321451200611
Figure BSA00000321451200621
Embodiment 37.5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-piperidin-4-yl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200622
Steps A: carbonyl 4-{5-allyl group-8-[(4-methyl piperidine-1-yl)]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2-yl } preparation of piperidines-1-carboxylic acid tert-butyl ester
Figure BSA00000321451200631
According to the general reduction amination method described in the embodiment 2, in room temperature, with NaBH (OAc) 3(200mg, 0.94mmol) add to 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (122mg, 0.61mmol), 5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, (111mg is in methylene dichloride 0.196mmol) (5mL) solution for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt.Reactant in stirred overnight at room temperature, with methylene dichloride (20mL) dilution, and is added 1N NaOH (2mL).This mixture was stirred 5 minutes, pass through the Hydromatrix post (10g) that is pre-charged with then, and with this Hydromatrix post washed with dichloromethane.Remove the intermediate that methylene dichloride obtains thick Boc-protection, it is used for next step without purifying.
Step B:5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-piperidin-4-yl-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200632
The intermediate of steps A is dissolved in methylene dichloride (10mL) and adds trifluoroacetic acid (3mL).With this mixture at stirring at room 30 minutes, the excessive TFA of vacuum-evaporation then.Resistates carries out purifying by preparation HPLC, obtains required product (62mg), and it is a tfa salt.MS(M+1)：421.3。 1H?NMR(600MHz，CD 3OD)δppm?1.09(d，J＝6.66Hz，3H)，1.14-1.39(m，2H)，1.63-1.97(m，3H)，2.16-2.30(m，2H)，2.62(d，J＝13.31Hz，2H)，2.88-3.05(m，1H)，3.13-3.23(m，1H)，3.23-3.31(m，2H)，3.36(t，J＝5.63Hz，2H)，3.76(d，J＝13.31Hz，2H)，3.82-4.02(m，4H)，4.62-4.85(m，3H)，4.88-4.96(m，3H)，5.25(d，J＝9.22Hz，1H)，6.04-6.16(m，1H)，7.36(d，J＝8.70Hz，1H)，7.57(d，J＝8.70Hz，1H)，7.70(s，1H)。C 28H 38N 4O 2.2C 2HF 3O 2.H 2The analytical calculation value of O: C, 54.23; H, 5.97; N, 7.91.Measured value: C, 54.49; H, 5.79; N, 7.91.
Embodiment 38.5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
At N 2Under the atmosphere, (50 μ L) adds to 5-allyl group-8-[(4-methyl piperidine-1-yl with 4-(brooethyl) tetrahydrochysene-2H-pyrans) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt (53mg, 0.093mmol) and Cs 2CO 3(200mg) in the de-gassed solution in DMF.This mixture was heated 1.5 hours in sealed tube at 110 ℃, make this mixture be cooled to room temperature, with methylene dichloride and water dilution, through too short Hydromatrix tube.With this organic solution vacuum concentration, resistates is by HPLC (10-65%CH 3CN, 30 minutes) carry out purifying, obtain required product (16mg), it is a tfa salt, MS (M+1): 436.1. 1H?NMR(600MHz，CD 3OD)δppm?1.09(d，J＝6.66Hz，3H)，1.15-1.37(m，2H)，1.38-1.61(m，3H)，1.63-1.98(m，5H)，2.34-2.48(m，1H)，2.82-3.04(m，1H)，3.10-3.39(m，4H)，3.47-3.54(m，1H)，3.56-3.65(m，2H)，3.65-3.74(m，1H)，3.81-4.13(m，5H)，4.46-4.56(m，1H)，4.62-4.78(m，1H)，4.85-4.97(m，3H)，5.25(d，J＝11.26Hz，1H)，6.10(d，1H)，7.35(d，J＝8.70Hz，1H)，7.56(d，J＝8.70Hz，1H)，7.71(s，1H)。
Embodiment 39.5-allyl group-2-(2,2-difluoro propionyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200642
In room temperature, with HATU (430mg 1.13mg) adds to 5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts (470mg, 0.83mmol), 2,2-difluoro propionic acid (147mg, 1.33mmol), in the mixture of diisopropyl ethyl amine (0.8mL) in DMF (5mL).With this reaction mixture stirring at room 30 minutes, vacuum concentration, and add water (10mL).This mixture is also dry with methylene dichloride (40mL) extraction.Remove and desolvate, obtain required product (365mg).The part crude product is by HPLC (25-85%CH 3CN) purifying obtains being used for specific pure products.MS(M+1)：430.1。According to the NMR data, title compound be two kinds of optically active isomers causing of amido linkage～3: 1 mixtures.
Embodiment 40.5-allyl group-2-(cyclopentylcarbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200651
In room temperature, pentamethylene formyl chloride (0.1mL) is added to 8-[(4-methyl piperidine-1-yl) carbonyl]-5-allyl group-2,3,4, in methylene dichloride (2mL) solution of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts (0.1mmol) and diisopropyl ethyl amine (0.3mL).This mixture stirring at room 1 hour, with methylene dichloride (10mL) dilution, and is added 1N NaOH (1mL).Make the short pad of this mixture through Hydromatrix then, with this organic solution vacuum concentration, resistates is by preparation HPLC (10-75%CH 3CN) carry out purifying and freeze-drying, obtain title compound (21mg).MS(M+1)：434.4。According to the NMR data, title compound is the mixture of two kinds of optically active isomers causing of amido linkage, is～1: 3 in the two ratio of room temperature.
Embodiment 41.5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
To the 8-[(4-methyl piperidine-1-yl that derives from embodiment 1D) carbonyl]-5-allyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles dihydrochloride (82mg, 0.20mmol), diisopropyl ethyl amine (0.15mL), (32.5mg is 0.25mmol) in the solution in DMF (3mL) for tetrahydrochysene-2H-pyrans-4-carboxylic acid, whole part ground adding HATU (95mg, 0.25mmol).With this mixture stirring at room 30 minutes.Evaporation DMF is dissolved in methylene dichloride with resistates and washes with water.With this dichloromethane solution vacuum concentration, resistates is by preparation HPLC (10-70%CH 3CN) purifying obtains the tfa salt (68mg) of title compound.MS(M+1)：450.0。According to the NMR data, title compound is the mixture of two kinds of optically active isomers causing of amido linkage, is～1: 3 in the two ratio of room temperature.
Embodiment 42.5-allyl group-2-(cyclopropyl carbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200661
According to the method for embodiment 41, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-allyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles dihydrochloride and cyclopropane-carboxylic acid, preparation title compound.MS(M+1)：406.0。According to the NMR data, title compound is the mixture of two kinds of optically active isomers causing of amido linkage, is～1: 3 in the two ratio of room temperature.
Embodiment 43.5-allyl group-2-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200662
According to the method for embodiment 41, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-allyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles dihydrochloride and butyric acid prepare title compound.MS(M+1)：408.0。According to the NMR data, title compound is the mixture of two kinds of optically active isomers causing of amido linkage, is～1: 3 in the two ratio of room temperature.
Embodiment 44.5-allyl group-N-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] indoles-2-methane amide
Figure BSA00000321451200663
To the 5-allyl group that derives from embodiment 1D, method B-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, in the solution of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (0.15mmol) in anhydrous DMA (2mL), add ethyl isocyanate (0.15mmol).With this mixture stirring at room 2 hours.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (27mg, 35%) of required product.MS(M+1)：409.0。 1H?NMR(400MHz，CDCl 3)δppm?1.00(d，J＝6.25Hz，3H)，1.19(t，J＝7.23Hz，3H)，1.20-1.30(m，2H)，1.62-1.85(m，2H)，2.80(t，J＝5.37Hz，2H)，2.88-3.10(m，2H)，3.35(q，J＝7.23Hz，2H)，3.90(t，J＝5.37Hz，2H)，4.54(s，2H)，4.62-4.71(m，2H)，4.86(d，J＝17.18Hz，1H)，5.15(d，J＝10.54Hz，1H)，5.29-5.68(m，3H)，5.83-5.96(m，1H)，7.18-7.30(m，2H)，7.61(s，1H)。
Embodiment 45.5-allyl group-N-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] indoles-2-methane amide
Figure BSA00000321451200671
According to the method identical, by 5-allyl group-8-[(4-methyl piperidine-1-yl with embodiment 44) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and n-Isopropyl isocyanate prepare title compound.MS(M+1)：423.0。 1H?NMR(400MHz，CDCl 3)δppm?1.00(d，J＝6.25Hz，3H)，1.15-1.30(m，2H)，1.21(d，J＝6.44Hz，6H)，1.69(m，3H)，2.80(t，J＝5.08Hz，2H)，2.96(s，2H)，3.91(m，2H)，4.04(m，1H)，4.52(s，2H)，4.66(m，2H)，4.87(d，J＝16.99Hz，1H)，5.14(t，J＝10.06Hz，1H)，5.95-6.00(m，4H)，7.18-7.31(m，2H)，7.62(s，1H)。
Embodiment 46.5-allyl group-2-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200672
To 5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] add triethylamine (0.18mmol) in the solution of indoles (0.15mmol) in anhydrous methylene chloride (2mL), then add cyclopropane SULPHURYL CHLORIDE (0.18mmol).With this mixture stirring at room 2 hours.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains required product (28mg).MS(M+1)：442.0。 1H?NMR(400MHz，CDCl 3)δppm?0.92-1.05(m，3H)，1.00(d，J＝6.25Hz，3H)，1.20-1.35(m，3H)，1.58-1.80(m，2H)，2.34(m，1H)，2.91(t，J＝5.62Hz，2H)，3.01-3.12(m?1H)，3.77(t，J＝5.62Hz，2H)，3.82-3.98(m，1H)，4.39-4.59(m，3H)，4.62(s，2H)，4.67(m，2H)，4.83(d，J＝16.99Hz，1H)，5.15(d，J＝10.35Hz，1H)，5.91(m，1H)，7.20-7.30(m，2H)，7.52(s，1H)。
Embodiment 47.5-allyl group-2-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200681
To 5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] add triethylamine (0.18mmol), the adding ethyl sulfonyl chloride (0.18mmol) that continues in the solution of indoles (0.15mmol) in anhydrous methylene chloride (2mL).With this mixture stirring at room 2 hours.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains required product (31mg).MS(M+1)：430.0。 1H?NMR(400MHz，CDCl 3)
Figure BSA00000321451200682
ppm?1.00(d，J＝6.25Hz，3H)，1.28(m，2H)，1.38(t，J＝7.35Hz，3H)，1.71(m，3H)，2.88(t，J＝5.56Hz，2H)，3.05(q，J＝7.35Hz，2H)，3.54(s，4H)，3.78(t，J＝5.56Hz，2H)，4.60(s，2H)，4.67(m，2H)，4.84(d，J＝17.18Hz，1H)，5.15(d，J＝10.35Hz，1H)，5.92(m，1H)，7.25(m，2H)，7.51(s，1H)。
Embodiment 48.5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200683
Steps A: 5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451200691
According to the general method described in the embodiment 1 step C, by 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester (2.40g) and 2-bromo-ethyl-methyl ether (1.0mL), preparation 5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester (1.35g, 49%).MS(M+1)：456.1。
Step B:5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts
Figure BSA00000321451200692
According to the method (method B) identical with embodiment 1 step D, by the 5-that derives from steps A (2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester (1.35g), two tfa salts (1.45g) of preparation title compound.
Step C:5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200693
By being similar to the method described in the embodiment 2, by 5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and tetrahydrochysene-4H-pyrans-4-ketone, the tfa salt of preparation title compound.MS(M+1)：440.0。 1H?NMR(600MHz，CD 3OD)δppm?0.83(d，J＝6.66Hz，3H)，0.92-1.15(m，2H)，1.39-1.70(m，3H)，1.71-1.83(m，2H)，2.02(m，2H)，2.63-2.78(m，1H)，2.88-3.02(m，1H)，3.08(s，3H)，3.15(bs，2H)，3.28-3.42(m，3H)，3.46-3.59(m，3H)，3.60-3.71(m，1H)，3.80-3.91(m，1H)，3.96(dd，J＝11.52，3.84Hz，2H)，4.23-4.13(m，2H)，4.31(d，J＝13.57Hz，1H)，4.52(d，J＝13.57Hz，2H)，7.09(d，J＝8.45Hz，1H)，7.34(d，J＝8.45Hz，1H)，7.42(s，1H)。
Embodiment 49-64. the following examples (table 3) are by 5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts, by with the preparation of plate method identical described in the embodiment 11-36.LCMS condition: 10-95%CH 3CN, 3 minutes.
Table 3
Figure BSA00000321451200701
Figure BSA00000321451200711
Figure BSA00000321451200721
Embodiment 65.2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200731
To 5-allyl group-2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, (56mg 0.14mmol) adds Pd/C (10mg) and also this mixture is placed H 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt in the solution in MeOH (6mL) 2(30psi).This mixture in stirred overnight at room temperature, is filtered then and concentrates.Gained oily matter (60mg) is by reversed-phase HPLC (5-75%CH 3CN) purifying obtains the tfa salt (30mg) of title compound.MS(M+1)：408.0。 1H?NMR(400MHz，CDCl 3)δppm?0.89(t，J＝14.84Hz，3H)，0.98(d，J＝6.44Hz，3H)，1.05-1.37(m，2H)，1.55-1.94(m，9H)，1.95-2.23(m，4H)，2.57-3.11(m，3H)，3.30-3.49(m，2H)，3.52-3.67(m，1H)，3.69-4.08(m，4H)，4.17(d，J＝13.86Hz，1H)，4.71(d，J＝14.25Hz，1H)，4.57-4.78(m，1H)，7.21(d，J＝8.60Hz，1H)，7.29(d，J＝8.60Hz，1H)，7.47(s，1H)。
Embodiment 66.8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200732
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-5-propyl group-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Method A: hydride process
5-allyl group-8-[(4-methyl piperidine-1-yl with embodiment 1 step C) carbonyl]-1,3,4, (1.10g 2.52mmol) is dissolved in methyl alcohol (40mL) to 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester, the Pd/C (100mg) of adding 10%, and with the H of this mixture at 30psi 2Following hydrogenation 2 hours.Leach Pd/C and, obtain required product (998mg, 90.3%) except that desolvating.MS(M+1)：440.1。
Method B: alkylation process
Figure BSA00000321451200741
Under 0 ℃ and nitrogen atmosphere, with 60%NaH (120mg 3.0mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (325mg is 0.819mmol) in the suspension in DMF (10mL) for the Indoline-2-carboxylic acid tert-butyl ester.With this mixture stirring at room 30 minutes, then room temperature add propyl iodide (402mg, 2.36mmol), and with reaction mixture stirring at room 1 hour.Solvent removed in vacuo is suspended in resistates in the water (10mL), collects faint yellow solid, and water (20mL) washing obtains crude product (365mg).Crude product is dissolved in methyl alcohol, and vacuum is removed methyl alcohol then, obtains required product (346mg, 96%).MS(M+1)：440.1。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
With 8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-1,3,4, (346mg 0.788mmol) is dissolved in methylene dichloride (8mL) and add trifluoroacetic acid (2mL) to 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester.With this mixture stirring at room 30 minutes.Vacuum is removed methylene dichloride and excessive trifluoroacetic acid (TFA), with the resistates freeze-drying, obtains required product (371mg), and it is a tfa salt.MS(M+1)：340.0。
Step C:8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(3,3, the 3-trifluoro propyl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200751
According to the general method of embodiment 1 step e, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt and 3,3,3-trifluoro propionic aldehyde prepares the tfa salt of required product.MS(M+1)：436.4。1HNMR(600Hz，CD 3OD)：δppm?1.02(t，J＝7.1Hz，3H)，1.07(d，J＝6.40Hz，3H)，1.26(m，2H)，1.60-1.95(m，5H)，2.85-3.25(m，4H)，3.37(s，2H)，3.79(t，J＝7.70Hz，2H)，3.95(m，3H)，4.24(s，2H)，4.70(m，3H)，7.35(d，J＝8.2Hz，1H)，7.61(d，J＝8.2Hz，1H)，7.65(s，1H)。
Embodiment 67.8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
According to the general method of embodiment 1 step e, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt and tetrahydrochysene-4H-pyrans-4-ketone prepares the tfa salt of required product.MS(M+1)：424.11。 1H?NMR(600MHz，CD 3OD)δppm?0.81(t，J＝7.17Hz，3H)，0.87(d，J＝6.14Hz，3H)，0.96-1.15(m，2H)，1.40-1.87(m，7H)，1.97-2.12(m，2H)，2.74(s，1H)，2.98(s，1H)，3.10-3.17(m，2H)，3.26-3.78(m，5H)，3.82-4.11(m，5H)，4.30-4.67(m，3H)，7.13(d，J＝9.22Hz，1H)，7.39(d，J＝9.22Hz，1H)，7.47(s，1H)。
Embodiment 68.8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(tetrahydrofuran (THF)-3-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200753
According to the general method of embodiment 1 step e, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts and tetrahydrofuran (THF)-3-formaldehyde prepare the tfa salt of required product.MS(M+1)：424.46。 1HNMR(400MHz，CD 3OD)δppm?0.91(t，J＝7.42Hz，3H)，0.96(d，J＝6.25Hz，3H)，1.01-1.27(m，2H)，1.50-1.88(m，6H)，2.15-2.33(m，1H)，2.76-2.95(m，2H)，3.08(d，J＝10.16Hz，1H)，3.18-3.27(m，2H)，3.43(d，J＝7.42Hz，2H)，3.47-3.65(m，2H)，3.68-4.03(m，5H)，4.12(t，J＝7.03Hz，2H)，4.25-4.46(m，1H)，4.50-4.67(m，1H)，4.67-4.85(m，1H)，7.22(dd，J＝8.59，1.56Hz，1H)，7.48(d，J＝8.59Hz，1H)，7.54(s，1H)。
Embodiment 69.2-(2,2-two fluoro ethyls)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200761
At N 2Under the atmosphere, with 1,1-two fluoro-2-iodoethane (50 μ L) add to 5-propyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts (100mg, 0.176mmol) and Cs 2CO 3(200mg) in the de-gassed solution in DMF (3mL).With this mixture in sealed tube in 140 ℃ of heating 4 hours, make this mixture be cooled to room temperature, with the dilution of methylene dichloride and water, through the Hydromatrix post.With this organic solution vacuum concentration, resistates is by HPLC (10-75%CH 3CN, 30 minutes) carry out purifying, obtain title compound (12mg), it is a tfa salt.MS(M+1)：404.1。 1H?NMR(400MHz，CD 3OD)δppm?0.92(t，J＝7.42Hz，3H)，0.96(d，J＝6.44Hz，3H)，1.03-1.27(m，2H)，1.49-1.92(m，5H)，2.73-3.17(m，3H)，3.26(s，1H)，3.81-3.97(m，5H)，4.13(t，J＝7.23Hz，2H)，4.47-4.65(m，1H)，4.68(s，2H)，6.51(tt，J＝53.50，3.60Hz，1H)，7.24(dd，J＝8.59，1.17Hz，1H)，7.50(d，J＝8.59Hz，1H)，7.53(d，J＝1.17Hz，1H)。
Embodiment 70. (1R*, 2R*)-2-{8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2-yl } cyclopentanol
Figure BSA00000321451200762
At N 2Under the atmosphere, 6-oxabicyclo [3.1.0] hexane (0.1mL) is added to 5-propyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts (63mg, 0.11mmol) and Cs 2CO 3(270mg) in the degassing mixture in DMF (3mL).This mixture 140 ℃ of heated overnight, is made it to be cooled to room temperature,, wash with water with the ether dilution.With this ethereal solution vacuum concentration, resistates is by preparation HPLC (5-65%CH 3CN) carry out purifying, obtain the tfa salt (13mg) of title compound.MS(M+1)：424.1。 1HNMR(600MHz，CD 3OD)：δppm?1.03(t，J＝7.2Hz，3H)，1.07(d，J＝6.1Hz，3H)，1.30(m，2H)，1.52-2.00(m，11H)，2.22(m，1H)，2.46(m，1H)，2.95(brs，1H)，3.19(brs，1H)，3.58-4.05(m，3H)，4.23(m，2H)，4.46-4.75(m，5H)，7.34(d，J＝8.2Hz，1H)，7.63(m，2H)。
Embodiment 71.8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-pyridine-2-base-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200771
At N 2Under the atmosphere,, 5-propyl group-8-[(4-methyl piperidine-1-yl) carbonyl with 2-bromopyridine (0.1mL)]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts (77mg, 0.135mmol) and Cs 2CO 3(100mg) degassing mixture in DMF (2mL) is 145 ℃ of heated overnight in sealed tube.Through being similar to work and the preparation HPLC (15-70%CH among the embodiment 62 3CN), obtain the tfa salt (16mg) of title compound.MS(M+1)：417.10； 1H?NMR(400MHz，CD 3OD)δppm?0.91(t，J＝7.42Hz，3H)，1.00(d，J＝6.25Hz，3H)，1.08-1.30(m，2H)，1.52-1.93(m，5H)，2.72-3.22(m，4H)，3.87(s，1H)，4.07-4.25(m，4H)，4.62(s，1H)，4.92(s，2H)，7.01(t，J＝6.64Hz，1H)，7.20-7.26(m，1H)，7.48(d，J＝8.59Hz，1H)，7.55-7.65(m，2H)，7.88-8.03(m，1H)，8.03-8.14(m，1H)。
Embodiment 72.8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(3,4,5,6-tetrahydropyridine-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200772
In room temperature, with 6-methoxyl group-2,3,4,5-tetrahydropyridine (0.3mL) adds to 5-propyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, (110mg is 138mg) in the solution in methyl alcohol (1mL) for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles four tfa salts.With this mixture in stirred overnight at room temperature, and by preparation HPLC (10-70%CH 3CN) purifying obtains the tfa salt (35mg) of title compound.MS(M+1)：421.10。 1H?NMR(400MHz，CD 3OD)δppm?0.89(t，J＝7.42Hz，3H)，0.97(d，J＝6.45Hz，3H)，1.01-1.29(m，2H)，1.48-2.01(m，10H)，2.74-2.94(m，3H)，2.97-3.12(m，3H)，3.48(q，J＝6.31Hz，2H)，3.82(s，1H)，3.98(t，J＝5.66Hz，2H)，4.05-4.16(m，2H)，4.58(s，1H)，4.74(s，1H)，7.15-7.24(m，1H)，7.41-7.57(m，2H)。
Embodiment 73.2-(3,4-dihydro-2 h-pyrrole-5-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200781
In room temperature, with 5-methoxyl group-3,4-dihydro-2 h-pyrrole (0.3mL) adds to 5-propyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, (110mg is 138mg) in the solution in methyl alcohol (1mL) for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles four tfa salts.With this mixture in stirred overnight at room temperature, and by preparation HPLC (10-70%CH 3CN) carry out purifying, obtain the tfa salt (31mg) of title compound.MS(M+1)：407.1。 1H?NMR(400MHz，CD 3OD)δppm?0.91(t，J＝7.42Hz，3H)，0.99(d，J＝6.44Hz，3H)，1.06-1.28(m，2H)，1.55-1.89(m，5H)，2.14-2.39(m，2H)，2.89(s，1H)，3.00-3.21(m，4H)，3.67-3.92(m，3H)，3.94-4.06(m，2H)，4.08-4.18(m，2H)，4.60(s，1H)，4.79-4.89(m，2H)，7.17-7.27(m，1H)，7.41-7.60(m，2H)。
Embodiment 74.2-(cyclobutyl carbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200782
To 8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (80mg 0.14mmol) and in methylene dichloride (5mL) solution of diisopropyl ethyl amine (0.2mL), adds tetramethylene formyl chloride (0.1mL) to indoles two tfa salts.This mixture stirring at room 3 minutes, is added 1N NaOH (1mL), and utilize methylene dichloride to make this mixture by Hydromatrix tube (10g) as elutriant.Solvent removed in vacuo, resistates is by preparation HPLC (20-75%CH 3CN) carry out purifying, obtain title compound (65mg).MS(M+1)：422.1。According to NMR spectrum, title compound is 2: 1 mixtures of the optically active isomer that causes of amido linkage.
Embodiment 75.2-(cyclopentylcarbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200791
According to the general method of embodiment 74, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles two tfa salts and pentamethylene formyl chloride, preparation title compound.MS(M+1)：436.1。According to NMR spectrum, title compound be the optically active isomer that causes of amido linkage～3: 1 mixtures.
Embodiment 76.2-(2,2-difluoro propionyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
With 5-allyl group-2-(2,2-difluoro propionyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3; 4,5-tetrahydrochysene-1H-pyrido [4, the 3-b] indoles (crude product of embodiment 39; 301mg), the hydrogenation under 30psi of the mixture of 10%Pd/C (40mg) in methyl alcohol (30mL) is spent the night.Filtering Pd/C, and remove methyl alcohol, obtain crude product (301mg).MS(M+1)：432.0。 1H?NMR(600MHz，CD 3OD)δppm?1.00(t，J＝7.42Hz，3H)，1.08(d，J＝6.40Hz，3H)，1.16-1.41(m，2H)，1.62-2.06(m，8H)，2.84-3.28(m，4H)，3.95(s，1H)，4.10-4.28(m，4H)，4.70(s，1H)，4.92(s，1H)，5.02-5.09(m，1H)，7.29(d，J＝8.45Hz，1H)，7.54(d，J＝8.45Hz，1H)，7.58-7.65(m，1H)。
Embodiment 77.2-(cyclopropyl methyl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Steps A: 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Under room temperature and nitrogen atmosphere, with 60%NaH (300mg 7.5mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (1.58g is 3.98mmol) in the suspension in DMF (30mL) for the Indoline-2-carboxylic acid tert-butyl ester.With this mixture stirring at room 20 minutes, then room temperature add the solution (10mL) of 4-ethoxy benzyl chlorine in DMF (by 4-oxyethyl group benzylalcohol (1.10g, 7.23mmol) and SOCl 2(1.0mL) freshly prepd in 0 ℃ in methylene dichloride), and with reaction mixture stirring at room 1 hour.Solvent removed in vacuo is dissolved in methylene dichloride with resistates and washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product, and it obtains required product (1.40mg, 66%) through silica gel (0-50%EtOAc/ methylene dichloride) purifying.MS(M+1)：532.2。
Step B:5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Method A: the preparation of hydrochloride
With 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, (600mg 1.12mmol) is dissolved in ethyl acetate (10mL) to 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester, and add 2N HCl/ diethyl ether solution, with this mixture in stirred overnight at room temperature.Remove and desolvate, obtain the crude product (562mg) of title compound, it is a HCl salt.
The preparation of method B:TFA salt
With 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, (1.35g 2.53mmol) is dissolved in methylene dichloride (20mL) to 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester, and add TFA (4mL), with this mixture stirring at room 1 hour.Remove TFA, obtain the tfa salt (1.85g) of required product.
Step C:2-(cyclopropyl methyl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
In room temperature, with NaBH (OAc) 3(160mg 0.758mmol) whole part adds to 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles dihydrochloride (230mg, 0.453mmol), in methylene dichloride (5mL) solution of cyclopanecarboxaldehyde (0.1mL).With this mixture stirring at room 30 minutes, with the methylene dichloride dilution, and with 1N NaOH solution washing.Dry and the vacuum concentration with organic layer.Resistates is by preparation HPLC (10-70%CH 3CN) carry out purifying, obtain the tfa salt (136mg) of title compound.MS(M+1)：486.1。 1H?NMR(400MHz，CD 3OD)δppm?0.43-0.53(m，2H)，0.72-0.88(m，2H)，1.00(d，J＝6.40Hz，3H)，1.05-1.30(m，3H)，1.33(t，J＝7.03Hz，3H)，1.52-1.86(m，3H)，2.75-3.22(m，5H)，3.26(d，J＝7.42Hz，2H)，3.49-3.64(m，1H)，3.81(s，1H)，3.97(q，J＝6.96Hz，2H)，4.43(d，J＝14.45Hz，1H)，4.60(s，1H)，4.79-4.87(m，1H)，5.30(d，J＝16.40Hz，1H)，5.41(d，J＝16.40Hz，1H)，6.81(d，J＝8.80Hz，2H)，7.02(d，J＝8.80Hz，2H)，7.25(dd，J＝8.49，1.56Hz，1H)，7.53(d，J＝8.49Hz，1H)，7.61(d，J＝1.56Hz，1H)。
C 31H 39N 3O 21.5C 2HF 3O 2The analytical calculation value: C, 62.18; H, 6.21; N, 6.40.Measured value: C, 61.80; H, 6.31; N, 6.46.
Embodiment 78.5-(4-ethoxy benzyl)-2-isobutyl--8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200821
Utilization is similar to the method described in the embodiment 77 step C, by 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles dihydrochloride and 2 methyl propanal, preparation title compound.MS(M+1)：488.1。 1H?NMR(400MHz，CD 3OD)δppm0.99(d，J＝6.44Hz，3H)，1.09(d，J＝3.71Hz，6H)，1.12-1.27(m，2H)，1.33(t，J＝7.03Hz，3H)，1.46-1.91(m，3H)，2.18-2.39(m，1H)，2.74-3.26(m，6H)，3.45-3.63(m，1H)，3.69-3.93(m，2H)，3.97(q，J＝7.03Hz，2H)，4.26-4.47(m，1H)，4.60(s，1H)，4.79(d，J＝14.45Hz，1H)，5.30(d，J＝16.40Hz，1H)，5.40(d，J＝16.40Hz，1H)，6.82(d，J＝8.80Hz，2H)，7.02(d，J＝8.80Hz，2H)，7.24(dd，J＝8.40，1.56Hz，1H)，7.52(d，J＝8.40Hz，1H)，7.61(d，J＝1.17Hz，1H)。
Embodiment 79.5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200822
Utilization is similar to the method described in the embodiment 77 step C, by 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles TFA and propionic aldehyde, preparation title compound.MS(M+1)：474.0。 1H?NMR(400MHz，CD 3OD)δppm?0.98(d，J＝6.44Hz，3H)，1.07(t，J＝7.42Hz，3H)，1.10-1.26(m，2H)，1.33(t，J＝7.03Hz，3H)，1.52-1.99(m，5H)，2.75-3.22(m，4H)，3.25-3.36(m，2H)，3.45-3.63(m，1H)，3.75-3.94(m，2H)，3.96(q，J＝7.03Hz，2H)，4.37(d，J＝14.45Hz，1H)，4.61(s，1H)，4.77(d，J＝14.25Hz，1H)，5.29(d，J＝16.20Hz，1H)，5.39(d，J＝16.20Hz，1H)，6.81(d，J＝8.79Hz，2H)，7.01(d，J＝8.79Hz，2H)，7.24(dd，J＝8.40，1.56Hz，1H)，7.51(d，J＝8.40Hz，1H)，7.59(d，J＝1.56Hz，1H)。
Embodiment 80.2-cyclobutyl-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200831
With sodium triacetoxy borohydride (65mg, 0.31mmol) add to 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (28 μ L are in methylene dichloride 0.37mmol) (2.5mL) solution for indoles (tfa salt and cyclobutanone by itself and MP-carbonate are freshly prepd).With this mixture in stirring at room, till not observing any raw material.Then with this mixture with methylene dichloride dilution and use saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt of required product, it is a white solid.(30mg, three steps 17%).MS(M+1)：486.0。 1H?NMR(400MHz，CDCl 3)δppm?0.97(d，J＝6.25Hz，3H)，1.02-1.30(m，2H)，1.36(t，J＝7.03Hz，3H)，1.49-1.87(m，4H)，1.86-2.02(m，1H)，2.21-2.37(m，2H)，2.51-2.71(m，2H)，2.73-3.09(m，2H)，2.82(d，J＝16.60Hz，1H)，3.10-3.34(m，2H)，3.56-3.86(m，3H)，3.95(q，J＝6.90Hz，3H)，4.59-4.73(m，2H)，5.09-5.25(m，2H)，6.78(d，J＝8.60，2H)，6.85(d，J＝8.60Hz，2H)，7.14-7.28(m，2H)，7.46(bs，1H)。
Embodiment 81.5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200832
Utilization is similar to the method described in the embodiment 77 step C, by 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles TFA and tetrahydrochysene-4H-pyrans-4-ketone, preparation title compound.MS(M+1)：516.15。 1H?NMR(600MHz，CD 3OD)δppm?1.08(d，J＝6.14Hz，3H)，1.15(m，2H)，1.42(t，J＝7.17Hz，3H)，1.50-2.07(m，5H)，2.19-2.32(m，2H)，2.95(s，1H)，3.11-3.35(m，2H)，3.49-3.69(m，3H)，3.71-3.83(m，1H)，3.91(s，1H)，4.06(q，J＝7.17Hz，2H)，4.21(d，J＝8.19Hz，2H)，4.61(d，J＝12.29Hz，1H)，4.70(s，1H)，4.83(d，J＝12.29Hz，1H)，5.39(d，J＝16.40Hz，1H)，5.51(d，J＝16.40Hz，1H)，5.58(s，2H)，6.91(d，J＝8.19Hz，2H)，7.11(d，J＝8.19Hz，2H)，7.35(d，J＝8.19Hz，1H)，7.63(d，J＝8.19Hz，1H)，7.72(s，1H)。
Embodiment 82.2-(cyclobutyl carbonyl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200841
Utilization is similar to the method described in the embodiment 74, and the preparation title compound is by 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles TFA and tetramethylene formyl chloride.MS(M+1)：514.2。According to the NMR data, title compound be two kinds of optically active isomers that cause by amido linkage～2: 1 mixtures.
Embodiment 83.5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-pyrimidine-2-base-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200842
At N 2Under the atmosphere, with 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salts (100mg), 2-bromo pyrimi piperidine (35mg), K 2CO 3(35mg) degassing mixture in DMF (2mL) heats (10 minutes, 100 ℃) under microwave condition, adds other 2-bromo pyrimi piperidine (18mg) then, K 2CO 3(35mg), and under microwave condition in 100 ℃ of reheat 10 minutes.Repeat this process once more.Make this mixture be cooled to room temperature and with methylene dichloride dilution, wash with water.With this organic solution vacuum concentration, resistates is by HPLC (20-80%CH 3CN) carry out purifying, obtain the tfa salt (28mg) of title compound.MS(M+1)：510.4。 1H?NMR(400MHz，CD 3OD)δppm?0.95(d，J＝6.44Hz，3H)，1.05-1.21(m，2H)，1.28(t，J＝7.03Hz，3H)，1.49-1.86(m，3H)，2.88(t，J＝5.57Hz，2H)，3.22-3.28(m，2H)，3.76-3.86(m，1H)，3.90(q，J＝7.03Hz，2H)，4.25(t，J＝5.76Hz，2H)，4.56(s，1H)，4.96(s，2H)，5.16-5.33(m，2H)，6.69-6.79(m，3H)，6.91(d，J＝8.79Hz，2H)，7.14(dd，J＝8.40，1.66Hz，1H)，7.38(d，J＝8.40Hz，1H)，7.55(d，J＝1.66Hz，1H)，8.43(d，J＝5.08Hz，2H)。
Embodiment 84.5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3,4,5,6-tetrahydropyridine-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200851
In room temperature, with 6-methoxyl group-2,3,4,5-tetrahydropyridine (0.3mL) adds to 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, in the solution of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salts (100mg) in methyl alcohol (1.5mL).This mixture is also passed through preparation HPLC (10-75%CH in stirred overnight at room temperature 3CN) carry out purifying, obtain the tfa salt (45mg) of title compound.MS(M+1)：513.1。 1H?NMR(400MHz，CD 3OD)δppm?0.99(d，J＝6.64Hz，3H)，1.06-1.27(m，2H)，1.33(t，J＝7.03Hz，3H)，1.51-2.01(m，6H)，2.86(t，J＝5.66Hz，2H)，2.98(t，J＝5.47Hz，2H)，3.03-3.15(m，1H)，3.30(s，2H)，3.43-3.55(m，2H)，3.74-3.92(m，1H)，3.96(m，4H)，4.50-4.69(m，1H)，4.78(s，1H)，4.90(s，1H)，5.29-5.35(m，2H)，6.78-6.84(m，2H)，6.98(d，J＝8.59Hz，2H)，7.21(t，J＝7.23Hz，1H)，7.44-7.50(m，1H)，7.53-7.62(m，1H)。
Embodiment 85.1-{5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2-yl } ethyliminum
With ethanimidic acid carbethoxy hydrochloride (30mg), diisopropyl ethyl amine (0.1mL) and 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles dihydrochlorides (33mg) are in methyl alcohol-CH 3Solution among the CN (2mL, 1: 1) heated 3 hours in sealed tube at 65 ℃.Solvent removed in vacuo, resistates is by HPLC (10-70%CH 3CN) carry out purifying, obtain two tfa salts of title compound.MS(M+1)：473.3。 1H?NMR(400MHz，CD 3OD)δppm?1.00(d，J＝6.25Hz，3H)，1.09-1.28(m，2H)，1.35(t，J＝7.03Hz，3H)，1.55-1.89(m，3H)，2.47(s，3H)，2.77-3.18(m，4H)，3.98(q，J＝7.03Hz，2H)，4.03(t，J＝5.47Hz，2H)，4.62(s，1H)，4.85(s，1H)，4.97(s，1H)，5.35(s，2H)，6.83(d，J＝8.59Hz，2H)，7.00(d，J＝8.59Hz，2H)，7.19-7.28(m，1H)，7.44-7.53(m，1H)，7.57(7.60)(s，1H)。Analytical calculation C 29H 36N 4O 22C 2HF 3O 2: C, 56.56; H, 5.46; N, 7.99.Measured value: C, 56.99; H, 5,45; N, 7.66.
Embodiment 86.2-(3,4-dihydro-2 h-pyrrole-5-yl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200861
Utilization is similar to the method described in the embodiment 84, by 5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt and 5-methoxyl group-3, the 4-dihydro-2 h-pyrrole, the preparation title compound.MS(M+1)：499.12。 1H?NMR(400MHz，CD 3OD)δppm?0.99(d，J＝6.44Hz，3H)，1.06-1.26(m，2H)，1.33(t，J＝7.03Hz，3H)，1.69(s，3H)，2.15-2.36(m，2H)，2.93-3.06(m，3H)，3.07-3.18(m，3H)，3.28-3.32(m，2H)，3.72-3.80(m，3H)，3.96(q，J＝7.03Hz，2H)，4.83(brs，2H)，4.91(brs，1H)，5.33(s，2H)，6.74-6.86(m，2H)，6.96-7.01(m，2H)，7.15-7.25(m，1H)，7.42-7.51(m，1H)，7.55(7.59)(d，J＝0.98Hz，1H)。
Embodiment 87.2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200862
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451200871
Under room temperature and nitrogen atmosphere, with 60%NaH (25mg 0.62mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (40mg is 0.10mmol) in the suspension in DMF (2mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture stirring at room 20 minutes, is added the solution (1mL) of 4-brooethyl tetrahydropyrans in DMF in room temperature then, and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo is dissolved in methylene dichloride with resistates and washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product (49mg), and it does not have purifying just to use.MS(M+1)：496.1。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200872
The thick intermediate (49mg) of steps A is dissolved in methylene dichloride (5mL), and adds TFA (1mL) in room temperature, with this mixture stirring at room 1.5 hours, and vacuum concentration.Resistates is dissolved in methylene dichloride once more and is carried on the short pad of silica gel usefulness methylene dichloride (20mL) washing.Use the NH of 2M then 3/ methyl alcohol washes out compound from post.Remove methyl alcohol, obtain title compound (38mg, two steps 96%).
Step C:2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200881
In room temperature, with NaBH (OAc) 3(67mg 0.32mmol) adds to 8-[(4-methyl piperidine-1-yl of step B) carbonyl]-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (38mg) are in the mixture of cyclopanecarboxaldehyde (0.1mL) in methylene dichloride (3mL).With this mixture stirring at room 1 hour, with the methylene dichloride dilution, with 1N NaOH washing, and vacuum concentration.Resistates is by preparation HPLC (15-75%CH 3CN) purifying obtains the tfa salt (12mg) of title compound.MS(M+1)：450.1。 1H?NMR(400MHz，CD 3OD)δppm?0.46-0.55(m，2H)，0.79-0.88(m，2H)，0.99(d，J＝6.64Hz，3H)，1.06-1.34(m，4H)，1.37-1.52(m，4H)，1.52-1.92(m，3H)，2.04-2.26(m，1H)，3.22-3.38(m，7H)，3.50-4.14(m，7H)，4.42(d，J＝14.45Hz，1H)，4.49-4.68(m，1H)，4.84(d，J＝14.45Hz，1H)，7.26(dd，J＝8.40，1.37Hz，1H)，7.49-7.61(m，2H)。
Embodiment 88.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-5-(sulfonyl propyl base)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Under room temperature and nitrogen atmosphere, with 60%NaH (120mg 3.0mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (397mg is 1.00mmol) in the suspension in DMF (20mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture stirring at room 1 hour, is dripped sulfonyl propyl chlorine (0.2mL) in room temperature then, and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo is dissolved in methylene dichloride with resistates and washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product, and it obtains title compound (225mg, 60%) by flash chromatography (elutriant 0-60% methylene dichloride is in EtOAc) purifying.MS(M+1)：504.1。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt
Figure BSA00000321451200891
8-[(4-methyl piperidine-1-yl with steps A) carbonyl]-5-(sulfonyl propyl base)-1,3,4; 5-tetrahydrochysene-2H-pyrido [4; 3-b] the Indoline-2-carboxylic acid tert-butyl ester (225mg 0.447mmol) is dissolved in methylene dichloride (2mL) and add TFA (2mL), and with this mixture stirring at room 1 hour.Vacuum is removed excessive TFA, with the resistates freeze-drying, obtains the tfa salt (235mg) of title compound.
Step C:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200892
With NaBH (OAc) 3(60mg 0.28mmol) adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3; 4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt (70mg; 0.135mmol), (50mg is in methylene dichloride 0.50mmol) (3mL) solution for tetrahydrochysene-pyrokomane.This mixture stirring at room 3 hours, is diluted with methylene dichloride.1N NaOH (1ml) is added in this mixture, this mixture was stirred 5 minutes, and be carried on the Hydromatrix tube of 10g.With compound methylene dichloride wash-out.Solvent removed in vacuo obtains crude product, and it is by preparation HPLC (10-70%CH 3CN) purifying and freeze-drying obtain the tfa salt (48mg) of title compound.MS(M+1)：488.1。 1H?NMR(600MHz，CD 3OD)δppm?0.97(t，J＝7.42Hz，3H)，0.99(d，J＝6.66Hz，3H)，1.05-1.30(m，2H)，1.44-1.86(m，5H)，1.87-2.00(m，2H)，2.18(d，J＝10.75Hz，2H)，2.78-2.94(m，1H)，3.12(t，J＝11.52Hz，1H)，3.36-3.62(m，7H)，3.65-3.79(m，2H)，3.83-4.08(m，1H)，4.13(dd，J＝11.65，3.71Hz，2H)，4.62(d，J＝8.70Hz，3H)，7.42(dd，J＝8.71，1.41Hz，1H)，7.53-7.77(m，1H)，8.05(d，J＝8.71Hz，1H)。C 26H 37N 3O 41.75C 2HF 3O 2The analytical calculation value: C, 51.50; H, 5.63; N, 6.11.Measured value: C, 51.07; H, 5.45; N, 6.07.
Embodiment 89.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200901
To crude product 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] (tfa salt, 30mg 0.06mmol) add 3 in the solution in anhydrous methylene chloride (2mL) to indoles; 3,3-trifluoro propionic aldehyde (0.12mmol) and sodium triacetoxy borohydride (0.09mmol).This mixture stirring at room 3 hours, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (18mg, 49%) of required product.MS(M+1)：500.0。 1H?NMR(600MHz，CDCl 3)δppm?1.04(t，J＝7.42Hz，3H)，1.09(d，J＝6.40Hz，3H)，1.23(s，br，1H)，1.35(s，br，1H)，1.75(m，4H)，1.89(s，br，1H)，2.93(m，3H)，3.14(s，br，1H)，3.27(m，2H)，3.51(m，2H)，3.58(s，br，2H)，3.63(s，br，2H)，3.83(s，br，1H)，4.42(s，br，2H)，4.77(s，br，1H)，7.48(d，J＝8.71Hz，1H)，7.57(s，1H)，8.09(d，J＝8.71Hz，1H)。
Embodiment 90.2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt
Figure BSA00000321451200902
According to being similar to the method described in the embodiment 89 step C, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt and cyclopentanone, preparation title compound.MS(M+1)：472.1。 1H?NMR(400MHz，CD 3OD)δppm?0.97(t，J＝7.13Hz，3H)，1.00(d，J＝6.25Hz，3H)，1.06-1.30(m，2H)，1.48-1.99(m，11H)，2.23-2.44(m，2H)，2.78-2.97(m，1H)，3.05-3.20(m，1H)，3.38-3.61(m，3H)，3.46(t，J＝7.81Hz，2H)，3.62-3.89(m，2H)，3.92-4.06(m，1H)，4.32-4.50(m，1H)，4.56-4.71(m，1H)，4.82(m，1H)7.42(dd，J＝8.60，0.98Hz，1H)，7.67(d，J＝0.98Hz，1H)，8.06(d，J＝8.60Hz，1H)。
Embodiment 91.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200911
Steps A: the preparation of dihydrofuran-3 (2H)-ketone
Figure BSA00000321451200912
In room temperature, to cross ruthenic acid tetrapropyl ammonium (TPAP, 20mg, 0.057mmol) add to tetrahydrofuran (THF)-3-alcohol (616mg, 7.0mmol), N-methylmorpholine N-oxide compound (NMO, 11mmol), in the mixture of activated molecular sieve powder (3.5g) in methylene dichloride (30mL), with reaction mixture stirring at room 2 hours, then by the short pad of diatomite (Ce1ite) filtration under diminished pressure.With the dichloromethane solution of dihydrofuran-3 (2H)-ketone (～20mL) as liquid storage (～0.3M).
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(tetrahydrofuran (THF)-3-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200913
According to being similar to the method described in the embodiment 89 step C, by dihydrofuran-3 (the 2H)-ketone and the 8-[(4-methyl piperidine-1-yl of steps A) carbonyl]-5-(sulfonyl propyl base)-2,3; 4; 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt, the preparation title compound.MS(M+1)：474.0。 1H?NMR(600MHz，CD 3OD)δppm?0.80-0.92(m，6H)，0.94-1.21(m，2H)，1.41-1.77(m，5H)，2.16-2.30(m，1H)，2.35-2.48(m，1H)，2.65-2.83(m，1H)，3.01(d，J＝8.19Hz，1H)，3.19(s，1H)，3.27-3.40(m，3H)，3.47-3.76(m，4H)，3.80-3.89(m，1H)，3.99-4.09(m，1H)，4.11-4.25(m，2H)，4.37-4.68(m，3H)，7.30(d，J＝9.22Hz，1H)，7.51(s，1H)，7.92(d，J＝9.22Hz，1H)。
Embodiment 92.2-(3,4-dihydro-2 h-pyrrole-5-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl table)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200921
Utilization is similar to the method described in the embodiment 86, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt and 5-methoxyl group-3,4-dihydro-2 h-pyrrole, preparation title compound.MS(M+1)：471.1。 1H?NMR(400MHz，CD 3OD)δppm?0.95(t，J＝7.42Hz，3H)，0.99(d，J＝6.44Hz，3H)，1.05-1.33(m，2H)，1.46-1.90(m，5H)，2.16-2.40(m，2H)，2.73-2.98(m，1H)，3.00-3.22(m，3H)，3.34-3.46(m，2H)，3.63-3.86(m，3H)，3.97(t，J＝5.76Hz，2H)，4.48-4.68(m，1H)，4.78(s，2H)，4.85-4.93(m，2H)，7.30-7.45(m，1H)，7.53(7.61)(s，1H)，7.99-8.08(m，1H)。
Embodiment 93.2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200922
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-5-(methyl sulphonyl)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451200931
Under 0 ℃ and nitrogen atmosphere, to 2-(tert-butoxycarbonyl)-2,3,4, (596mg, 1.5mmol) in the solution in dry DMF (20mL), whole part of ground adds 60%NaH (7.5mmol) to 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid.This mixture stirring at room 30 minutes, is added methylsulfonyl chloride (7.5mmol) in room temperature then lentamente, and with reaction mixture stirring at room 5 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride (80mL), dried over sodium sulfate is used in water (20mL) washing.Removing desolvates obtains crude product, and it carries out purifying by silica gel (5-60%EtOAc/ methylene dichloride), obtains required product, and it is yellow oil (520mg, 73%).MS(M+1)：476.0。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200932
To 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-1,3,4, (145mg is 0.31mmol) in two for 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451200933
In the solution in the alkane (3mL), add 4N HCl/ two
Figure BSA00000321451200934
Alkane (2mL).With this solution stirring at room 3 hours.Solvent removed in vacuo, resistates washs with diethyl ether, filters, and obtains the HCl salt (112mg, 96%) of required product, and it need not to be further purified and can use.MS(M+1)：376.0。
Step C:2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200935
To 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles (HCl salt; 56mg 0.13mmol) in the solution in anhydrous methylene chloride (4mL), adds cyclopentanone (0.26mmol) and sodium triacetoxy borohydride (0.39mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Solution (5mL) washing, and use Na 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (28mg) of required product.MS(M+1)：444.0。 1H?NMR(600MHz，CDCl 3)δppm?1.01(d，J＝6.14Hz，3H)，1.15(m，1H)，1.30(m，1H)，1.59-1.78(m，5H)，1.95(m，2H)，2.10(m，2H)，2.20(m，2H)，2.84(m，1H)，3.09(s，3H)，3.28(m，1H)，3.44(m，2H)，3.61(m，2H)，3.76(m，1H)，3.92(m，1H)，4.05(d，J＝14.23Hz，1H)，4.69(m，1H)，4.76(d，J＝14.23Hz，1H)，7.38(d，J＝8.25Hz，1H)，7.52(s，1H)，8.01(d，J＝8.25Hz，1H)。
Embodiment 94.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200941
According to the identical method of embodiment 93 step C, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3; 4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (HCl salt; 56mg, 0.13mmol) and tetrahydrochysene-4H-pyrans-4-ketone, the tfa salt of preparation title compound.MS(M+1)：460.0。 1H?NMR(600MHz，CDCl 3)δppm?1.01(d，J＝6.14Hz，3H)，1.15(m，1H)，1.28(m，1H)，1.70(m，2H)，1.83(m，1H)，2.03(m，2H)，2.12(m，2H)，2.85(m，1H)，3.10(m，3H)，3.08(s，3H)，3.30(m，1H)，3.51(m，3H)，3.71(m，2H)，3.87(m，1H)，4.19(m，2H)，4.66(m，2H)，7.39(d，J＝8.35Hz，1H)，7.53(s，1H)，8.02(d，J＝8.35Hz，1H)。
Embodiment 95.2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200942
According to the identical method of embodiment 93 step C, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and cyclobutanone, the preparation title compound tfa salt.MS(M+1)：430.0。 1H?NMR(400MHz，CD 3OD)δppm?0.96(d，J＝6.45Hz，3H)，1.04-1.27(m，2H)，1.50-1.58(m，1H)，1.64-1.74(m，1H)，1.73-1.80(m，1H)，1.85-1.99(m，2H)，2.26-2.38(m，2H)，2.41-2.52(m，2H)，2.78-2.90(m，1H)，3.05-3.14(m，1H)，3.28-3.30(m，3H)，3.32-3.57(m，3H)，3.63-3.74(m，1H)，3.75-3.82(m，1H)，3.86-4.02(m，1H)，4.12-4.22(m，1H)，4.54-4.62(m，1H)，4.64-4.75(m，1H)，7.40(d，J＝8.59Hz，1H)，7.61(s，1H)，8.04(d，J＝8.59Hz，1H)。
Embodiment 96.2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200951
According to the identical method of embodiment 93 step C, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and cyclopanecarboxaldehyde, the preparation title compound.MS(M+1)：430.0。 1H?NMR(400MHz，CD 3OD)δppm?0.50(d，J＝4.10Hz，2H)，0.78-0.87(m，2H)，0.97(d，J＝6.45Hz，3H)，1.06-1.34(m，3H)，1.54-1.62(m，1H)，1.64-1.74(m，1H)，1.75-1.85(m，1H)，2.78-2.90(m，1H)，3.01-3.17(m，1H)，3.29(s，3H)，3.27-3.30(m，2H)，3.38-3.50(m，2H)，3.51-3.62(m，1H)，3.65-3.75(m，1H)，3.91-4.02(m，1H)，4.35-4.46(m，1H)，4.55-4.63(m，1H)，4.76-4.84(m，1H)，7.41(dd，J＝8.59Hz，1H)，7.62(s，1H)，8.05(d，J＝8.59Hz，1H)。
Embodiment 97.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
According to the identical method of embodiment 93 step C, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and 3,3,3-trifluoro propionic aldehyde, the preparation title compound tfa salt.MS(M+1)：472.0。 1H?NMR(400MHz，CD 3OD)δppm?0.96(d，J＝6.45Hz，3H)，1.10-1.20(m，2H)，1.54-1.87(m，2H)，2.84-3.00(m，4H)，3.01-3.16(m，1H)，3.29(s，3H)，3.41-3.50(m，2H)，3.64-3.72(m，4H)，3.74-3.82(m，2H)，4.55-4.66(m，2H)，7.41(d，J＝8.59，1H)，7.59(s，1H)，8.04(d，J＝8.59Hz，1H)。
Embodiment 98.5-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200961
Steps A: 5-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451200962
Under 0 ℃ and nitrogen atmosphere, to 2-(tert-butoxycarbonyl)-2,3,4, in 5-tetrahydrochysene-1H-pyrido [4, the 3-b] indoles-solution of 8-carboxylic acid (0.5mmol) in dry DMF (4mL), whole part of ground adds 60%NaH (1.0mmol).This mixture stirring at room 30 minutes, is added methylsulfonyl chloride (1.0mmol) in room temperature then lentamente, and with reaction mixture in stirred overnight at room temperature.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride (20mL), dried over sodium sulfate is used in water (10mL) washing.Removing desolvates obtains crude product, and it need not to be further purified and promptly can be used for next step.MS(M+1)：502.07。
Step B:5-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200971
To thick 5-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (0.5mmol) are in two
Figure BSA00000321451200972
In the solution in the alkane (3mL), add the HCl/ two of 4N
Figure BSA00000321451200973
Alkane (2mL).With this solution stirring at room 3 hours.Solvent removed in vacuo, resistates need not to be further purified and can use.MS(M+1)：402.0。
Step C:5-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200974
To thick 5-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2; 3,4,5-tetrahydrochysene-1H-pyrido [4; 3-b] in the solution of indoles in anhydrous methylene chloride (4mL), add tetrahydrochysene-4H-pyrans-4-ketone (0.5mmol) and sodium triacetoxy borohydride (1.0mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (38mg, three step 13%) of required product.MS(M+1)：486.0。 1H?NMR(600MHz，CDCl 3)δppm1.01(d，J＝6.42Hz，3H)，0.97-1.09(m，2H)，1.17(m，1H)，1.32(m，3H)，1.70(m，2H)，1.82(m，1H)，2.03(m，2H)，2.12(m，2H)，2.60(m，1H)，2.85(m，1H)，3.22(m，3H)，3.51(m，3H)，3.58(m，1H)，3.75(m，2H)，3.89(m，1H)，4.19(d，J＝8.71Hz，2H)，4.68(m，2H)，7.36(d，J＝8.45Hz，1H)，7.52(s，1H)，8.03(d，J＝8.45Hz，1H)。
Embodiment 99.2-cyclopentyl-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200981
Steps A: 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451200982
Under room temperature and nitrogen atmosphere, with 60%NaH (140mg 3.50mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (400mg is 1.00mmol) in the suspension in DMF (10mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, room temperature add ethyl chloride (0.12mL, 1.27mmol), and with reaction mixture stirring at room 3 hours.Solvent removed in vacuo is dissolved in methylene dichloride with resistates and washes with water, with dried over sodium sulfate and concentrating under reduced pressure.Crude product is by adopting 5-75%CH 3The reversed-phase HPLC purifying of CN obtains the tfa salt (0.36g, 73%) of required compound.MS(M+1)490.4。
Step B:5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
With 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4; 5-tetrahydrochysene-2H-pyrido [4; 3-b] (0.36g 0.73mmol) is dissolved in methylene dichloride (5mL) to the Indoline-2-carboxylic acid tert-butyl ester, and trifluoroacetic acid (0.5mL) is added in the reaction mixture.With this mixture in stirring at room, till raw material disappears.Vacuum is removed excessive trifluoroacetic acid, obtains the trifluoroacetic acid salt form of required product.Then this salt is dissolved in methyl alcohol (6mL) and adds MP carbonate (1.52g).This mixture was stirred 1 hour, filter then and concentrate.Under the situation that does not need to be further purified, this unhindered amina is used for next step then.MS(M+1)：390.31。
Step C:2-cyclopentyl-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200991
With sodium triacetoxy borohydride (60mg; 0.28mmol) add to 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles (71mg, 0.18mmol) and cyclopentanone (33 μ L are 0.37mmol) in the mixture in methylene dichloride (3mL).With this mixture in stirring at room, till not observing any raw material.Then with this mixture with methylene dichloride dilution and use saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (8.5mg) of required product.MS(M+1)：458.0。 1H?NMR(600MHz，CD 3OD)：δppm?0.87(d，J＝6.66Hz，3H)，0.94-1.16(m，2H)，1.10(t，J＝7.30Hz，3H)，1.44-1.54(m，1H)，1.54-1.83(m，8H)，2.14-2.27(m，2H)，2.75(t，J＝11.65Hz，1H)，3.00(t，J＝11.65Hz，1H)，3.24-3.48(m，3H)，3.39(q，J＝7.34Hz，2H)，3.59(d，J＝11.65Hz，1H)，3.67-3.75(m，1H)，3.81-3.93(m，1H)，4.29(d，J＝14.59Hz，1H)，4.50(d，J＝11.01Hz，1H)，4.68(d，J＝14.08Hz，1H)，7.30(d，J＝8.70Hz，1H)，7.54(s，1H)，7.92(d，J＝8.70Hz，1H)。
Embodiment 100.5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451200992
With sodium triacetoxy borohydride (60mg; 0.28mmol) add to 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles (72mg, 0.18mmol) and tetrahydrochysene-4H-pyrans-4-ketone (34 μ L are 0.37mmol) in the mixture in methylene dichloride (3mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt of required product, it is white solid (18mg).MS(M+1)：474.0。 1H?NMR(600MHz，CD 3OD)δppm?0.89(d，J＝6.40Hz，3H)，0.59-1.09(m，2H)，1.13(t，J＝7.42Hz，3H)，1.47-1.76(m，3H)，1.77-1.89(m，2H)，2.08(d，J＝12.29Hz，2H)，2.70-2.83(m，1H)，2.96-3.08(m，1H)，3.29-3.47(m，5H)，3.42(q，J＝7.25Hz，2H)，3.55-3.70(m，2H)，3.85-4.00(m，1H)，4.03(dd，J＝11.65，4.48Hz，2H)，4.34-4.70(m，3H)，7.32(d，J＝8.45Hz，1H)，7.56(s，1H)，7.95(d，J＝8.45Hz，1H)。
Embodiment 101.2-cyclobutyl-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201001
With sodium triacetoxy borohydride (100mg; 0.47mmol) add to 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles TFA (90mg, 0.23mmol) and cyclobutanone (38 μ L are 0.51mmol) in the mixture in methylene dichloride (2mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (24mg) of required product.MS(M+1)：444.0。 1H?NMR(400MHz，CDCl 3)δppm?0.97(d，J＝6.25Hz，3H)，1.01-1.31(m，2H)，1.15(t，J＝7.32Hz，2H)，1.53-1.90(m，4H)，1.97(q，J＝9.96Hz，1H)，2.24-2.38(m，2H)，2.57-2.71(m，2H)，2.73-2.88(m，1H)，2.93-3.12(m，2H)，3.23(q，J＝6.58Hz，2H)，3.28-3.40(m，1H)，3.40-3.86(m，5H)，4.54-4.73(m，2H)，7.32(d，J＝8.40Hz，1H)，7.41(s，1H)，7.94(d，J＝8.40Hz，1H)。
Embodiment 102.2-(cyclopropyl methyl)-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201011
With sodium triacetoxy borohydride (100mg; 0.47mmol) add to 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles TFA (90mg, 0.23mmol) and cyclopanecarboxaldehyde (38 μ L are 0.51mmol) in the mixture in methylene dichloride (2mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (11mg) of required product.MS(M+1)：444.0。 1H?NMR(400MHz，CDCl 3)δppm?0.46(d，J＝3.71Hz，2H)，0.76-0.87(m，2H)，0.82(m，2H)，0.97(d，J＝6.45Hz，3H)，1.05-1.31(m，2H)，1.17(t，J＝7.32Hz，3H)，1.55-1.86(m，3H)，2.57-2.90(m，1H)，2.93-3.17(m，2H)，3.17-3.44(m，4H)，3.60-3.43(m，1H)，3.63-3.79(m，1H)，3.88-4.01(m，1H)，4.09(d，J＝7.32Hz，1H)，4.66(bs，1H)，4.78(d，J＝14.65Hz，1H)，7.33(d，J＝8.40Hz，1H)，7.47(s，1H)，7.95(d，J＝8.40Hz，1H)。
Embodiment 103.5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
According to the method that is similar to embodiment 94 step C, by 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles TFA and dihydrofuran-3 (2H)-ketone, preparation title compound.MS(M+1)：459.98。 1H?NMR(400MHz，CD 3OD)δppm?0.99(d，J＝6.44Hz，3H)，1.07-1.19(m，2H)，1.21(t，J＝7.32Hz，3H)，1.45-1.92(m，3H)，2.21-2.43(m，1H)，2.42-2.62(m，1H)，2.74-2.96(m，1H)，3.00-3.20(m，1H)，3.38-3.56(m，4H)，3.58-3.85(m，2H)，3.65(s，1H)，3.79(q，J＝8.01Hz，2H)，3.95(dd，J＝10.94，6.05Hz，1H)，4.02-4.19(m，1H)，4.19-4.38(m，2H)，4.60(s，2H)，7.41(dd，J＝8.59，1.56Hz，1H)，7.64(d，J＝1.17Hz，1H)，8.04(d，J＝8.59Hz，1H)。C 24H 33N 3O 4S2C 2HF 3O 20.5H 2The analytical calculation value of O: C, 48.27; H, 5.21; N, 6.03.Measured value: C, 48.44; H, 4.81; N, 6.01.
Embodiment 104.2-(2,2-two fluoro ethyls)-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201021
With 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salts (0.179mmol), K 2CO 3(110mg, 0.797mmol) purging with nitrogen gas is used in the mixture vacuum outgas in DMF (2.5mL) then, repeats the degassing and purge process three times, adds 1 then, 1-two fluoro-2-iodoethane (50uL).This mixture was heated 2 hours in sealed tube at 140 ℃, make it to be cooled to room temperature, with methylene dichloride (50mL) and water (5mL) dilution.This mixture was stirred 10 minutes, through the pre-Hydromatrix tube of filling of 10g.Removing desolvates obtains crude product, and it is by preparation HPLC (10-70%CH 3CN) purifying obtains the tfa salt (31mg) of title compound.MS(M+1)：454.0。 1H?NMR(600MHz，CD 3OD)δppm?0.99(d，J＝6.40Hz，3H)，1.04-1.17(m，2H)，1.22(t，J＝7.30Hz，3H)，1.53-1.64(m，1H)，1.65-1.75(m，1H)，1.75-1.88(m，1H)，2.79-2.93(m，J＝8.96Hz，1H)，3.04-3.19(m，1H)，3.41(s，2H)，3.49(q，J＝7.30Hz，2H)，3.64-3.86(m，5H)，4.54(s，2H)，4.61(d，J＝11.78Hz，1H)，6.46(dt，J＝53.89，3.07Hz，1H)，7.40(dd，J＝8.45，1.41Hz，1H)，7.59(s，1H)，8.05(d，J＝8.45Hz，1H)。
Embodiment 105.5-(sec.-propyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201022
Steps A: 5-(sec.-propyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201031
Under room temperature and nitrogen atmosphere, with 60%NaH (56mg 1.40mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (150mg is 0.38mmol) in the suspension in DMF (6mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, add propane-2-SULPHURYL CHLORIDE (55 μ L, 0.49mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product, and it is by preparation HPLC (5-75%CH 3CN) purifying obtains required product (50mg).MS(M+l)：504.4。
Step B:5-(sec.-propyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201032
With 5-(sec.-propyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4; 5-tetrahydrochysene-2H-pyrido [4; 3-b] (50mg 0.08mmol) is dissolved in methylene dichloride (2mL) to the Indoline-2-carboxylic acid tert-butyl ester, and trifluoroacetic acid (0.2mL) is added in the reaction mixture.Stir this mixture, till raw material disappears.Vacuum is removed excessive trifluoroacetic acid, obtains the trifluoroacetic acid salt form (47mg) of crude product.MS(M+1+CH 3CN)：445.40。Then this salt is neutralized with MP carbonate: 0.18g MP carbonate is added in the solution of above-mentioned salt in MeOH (1mL) and with this mixture stirred 1 hour, filter then and concentrate.
Step C:5-(sec.-propyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201041
With sodium triacetoxy borohydride (37mg; 0.17mmol) add to 5-(sec.-propyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles (47mg, 0.12mmol) and tetrahydrochysene-4H-pyrans-4-ketone (13 μ L are 0.14mmol) in the mixture in methylene dichloride (3mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (8mg) of required product.MS(M+1)：488.0。 1H?NMR(600MHz，CD 3OD)δppm?0.88(d，J＝6.66Hz，3H)，0.93-1.23(m，3H)1.18(d，J＝6.40Hz，6H)，1.44-1.55(m，1H)，1.55-1.64(m，1H)，1.65-1.74(m，1H)，1.77-1.88(m，2H)，2.07(d，J＝11.01Hz，2H)，2.69-2.81(m，1H)，3.01(t，J＝12.29Hz，2H)，3.27-3.50(m，2H)，3.40(t，J＝11.65Hz，2H)，3.53-3.67(m，3H)，4.02(dd，J＝11.65，4.22Hz，2H)，4.33-4.72(m，2H)，4.51(d，J＝10.75Hz，1H)，7.30(d，J＝8.70Hz，1H)，7.55(s，1H)，7.92(d，J＝8.70Hz，1H)。
Embodiment 106.N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide
Figure BSA00000321451201042
Steps A: the alkylsulfonyl 5-[(dimethylamino)]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201051
Under room temperature and nitrogen atmosphere, with 60%NaH (463mg 11.6mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (823mg is 2.07mmol) in the suspension in DMF (20mL) for the Indoline-2-carboxylic acid tert-butyl ester.With this mixture stirring at room 1 hour, then room temperature drip the dimethylamino SULPHURYL CHLORIDE (1.10g, 7.69mmol), and with reaction mixture stirring at room 2 hours, with 1N NaOH (6mL) cancellation.Solvent removed in vacuo also is dissolved in methylene dichloride with resistates, washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product (1.04g), and it is used for next step without purifying.MS(M+1)：505.0。
Step B:N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3, the preparation of 4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide tfa salt
Figure BSA00000321451201052
5-[(dimethylamino with steps A) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-1; 3; 4; (1.01g 2.00mmol) is dissolved in TFA (10mL) to 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester; and with this mixture stirring at room 1 hour; vacuum is removed TFA then, and resistates and methyl alcohol coevaporation obtain crude product (1.60g).With crude product water-soluble-acetonitrile and freeze-drying, obtain the tfa salt (1.07g) of title compound.
Step C:N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3, the preparation of 4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide
Figure BSA00000321451201061
Utilization is similar to the method described in the embodiment 93 step C, by N, and N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide tfa salt and tetrahydrochysene-pyrokomane, preparation title compound.MS(M+1)：489.0。 1H?NMR(600MHz，CD 3OD)δppm?1.01(t，J＝6.91Hz，3H)，1.06-1.33(m，2H)，1.61(s，1H)，1.73(s，1H)，1.82(s，1H)，1.89-2.03(m，2H)，2.11-2.29(m，2H)，2.89(s，3H)，2.91(s，3H)，3.14(s，1H)，3.37-3.65(m，6H)，3.67-3.81(m，2H)，3.95-4.10(m，1H)，4.11-4.20(m，2H)，4.53(s，1H)，4.64(s，1H)，4.75(s，1H)，7.37-7.47(m，1H)，7.65(7.67)(s，1H)，8.09(8.10)(d，J＝8.32Hz，1H)。
Embodiment 107.N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3,3, the 3-trifluoro propyl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide
Figure BSA00000321451201062
Utilization is similar to the method described in the embodiment 93 step C, by N, and N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide tfa salt and 3,3,3-trifluoro propionic aldehyde, preparation title compound.MS(M+1)：501.0。 1H?NMR(400MHz，CD 3OD)δppm?0.96(d，J＝6.25Hz，3H)，1.04-1.36(m，2H)，1.48-1.86(m，3H)，2.85(s，6H)，2.86-3.17(m，4H)，3.44(t，J＝5.86Hz，2H)，3.59-3.86(m，5H)，4.59(s，3H)，7.37(dd，J＝8.59，1.17Hz，1H)，7.57(d，J＝1.17Hz，1H)，8.05(d，J＝8.59Hz，1H)。
Embodiment 108.2-cyclopentyl-N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide
Figure BSA00000321451201071
Utilization is similar to the method described in the embodiment 93 step C, by N, and N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide tfa salt and cyclopentanone, preparation title compound.MS(M+1)：473.01。 1H?NMR(400MHz，CD 3OD)δppm0.96(d，J＝6.64Hz，3H)，1.02-1.30(m，2H)，1.49-1.96(m，9H)，2.22-2.36(m，2H)，2.79-2.90(m，1H)，2.85(s，6H)，2.97-3.17(m，1H)，3.32-4.03(m，6H)，4.32-4.81(m，3H)，7.36(dd，J＝8.59，1.56Hz，1H)，7.62(dd，J＝1.56，0.78Hz，1H)，8.04(dd，J＝8.59，0.78Hz，1H)。C 25H 36N 4O 3S1.25C 2H F 3O 2H 2The analytical calculation value of O: C, 52.16; H, 6.25; N, 8.84.Measured value: C, 52.14; H, 6.46; N, 8.51.
Embodiment 109.N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide
Utilization is similar to the method described in the embodiment 93 step C, by N, and N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide tfa salt and dihydrofuran-3 (2H)-ketone, the tfa salt of preparation title compound.MS(M+1)：475.02。 1H?NMR(400MHz，CD 3OD)δppm?0.97(d，J＝6.64Hz，3H)，1.04-1.29(m，2H)，1.50-1.87(m，3H)，2.22-2.38(m，1H)，2.43-2.59(m，1H)，2.80(d，J＝0.78Hz，1H)，2.84-2.87(m，6H)，2.99-3.17(m，1H)，3.38-3.51(m，2H)，3.63-3.84(m，4H)，3.93(dd，J＝11.13，6.05Hz，1H)，4.09-4.18(m，1H)，4.19-4.33(m，2H)，4.43-4.75(m，3H)，7.37(dd，J＝8.59，1.56Hz，1H)，7.60(d，J＝1.56Hz，1H)，8.05(d，J＝8.59Hz，1H)。
Embodiment 110.2-cyclobutyl-N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide
Figure BSA00000321451201081
Utilization is similar to the method described in the embodiment 93 step C, by N, and N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide tfa salt and cyclobutanone, preparation title compound.MS(M+1)：459.01。 1H?NMR(400MHz，CD 3OD)δppm0.96(d，J＝6.64Hz，3H)，1.00-1.29(m，2H)，1.41-2.05(m，5H)，2.13-2.56(m，4H)，2.69-2.96(m，1H)，2.85(s，6H)，2.95-3.19(m，1H)，3.30-3.53(m，3H，)3.58-4.01(m，3H)，4.05-4.29(m，1H)，4.35-4.79(m，2H)，7.36(dd，J＝8.01，1.17Hz，1H)，7.59(d，J＝1.17Hz，1H)，8.04(d，J＝8.01Hz，1H)。C 24H 34N 4O 3S1.75C 2HF 3O 2The analytical calculation value: C, 50.18; H, 5.47; N, 8.51.Measured value: C, 50.00; H, 4.33; N, 8.09.
Embodiment 111.N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide
Figure BSA00000321451201082
Steps A: the carbonyl 5-[(dimethylamino)]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201083
According to the method that is similar to embodiment 105 steps A, by 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester and dimethylaminoethyl chloride, preparation title compound.MS(M+1)：469.10。
Step B:N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide tfa salt
Figure BSA00000321451201091
According to the method that is similar to embodiment 93 step B, by the 5-[(dimethylamino) carbonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester and TFA/ methylene dichloride, the tfa salt of preparation title compound.MS(M+1)：369.1。
Step C:N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3, the preparation of 4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide
Figure BSA00000321451201092
According to the method that is similar to embodiment 93 step C, by N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide tfa salt and tetrahydrochysene-pyrokomane, the tfa salt of preparation title compound.MS(M+1)：453.1。 1H?NMR(600MHz，CD 3OD)δppm?1.01(d，J＝6.66Hz，3H)，1.08-1.31(m，2H)，1.58-1.88(m，3H)，1.89-2.02(m，2H)，2.20(d，J＝11.26Hz，2H)，2.89(s，1H)，3.02-3.18(m，2H)，3.10(s，6H)，3.23-3.40(m，1H)，3.50-3.56(t，J＝11.52Hz，2H)，3.54-3.65(m，1H)，3.69-3.87(m，2H)，4.02(s，1H)，4.15(dd，J＝11.26，4.10Hz，2H)，4.47-4.80(m，3H)，7.39(d，J＝8.70Hz，1H)，7.48(d，J＝8.70Hz，1H)，7.67(s，1H)。C 26H 36N 4O 31.75C 2HF 3O 2The analytical calculation value: C, 54.33; H, 5.83; N, 8.59.Measured value: C, 54.42; H, 5.81; N, 8.42.
Embodiment 112.2-cyclobutyl-NN-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide
Figure BSA00000321451201101
According to the method that is similar to embodiment 111, by N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide tfa salt and cyclobutanone, the tfa salt of preparation title compound.MS(M+1)：423.0(M+1)。1HNMR(400MHz，CD 3OD)δppm0.97(d，J＝6.45Hz，3H)，1.04-1.33(m，2H)，1.36-2.07(m，5H)，2.18-2.57(m，4H)，2.73-2.96(m，1H)，2.95-3.16(m，2H)，3.06(s，6H)，3.16-3.43(m，2H)，3.65-3.85(m，2H)，3.86-4.03(m，1H)，4.08-4.27(m，1H)，4.48-4.78(m，2H)，7.35(dd，J＝0.98，8.40，1H)，7.42(d，J＝8.40Hz，1H)，7.61(d，J＝0.98Hz，1H)。
Embodiment 113.5-butyryl radicals-2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201102
Steps A: carbonyl 5-butyryl radicals-8-[(4-methyl piperidine-1-yl)]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201103
Under room temperature and nitrogen atmosphere, with 60%NaH (58mg 1.45mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (400mg is 1mmol) in the suspension in DMF (10mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 1 hour, and (0.12mL 1.20mmol), and makes reaction mixture be warming up to room temperature to drip butyryl chloride at-20 ℃.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product, and it offers preparation HPLC (5-80%CH 3CN) purifying obtains title compound (363mg, 62%).MS(M+1)：468.4。
Step B:5-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201111
With 5-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester is dissolved in methylene dichloride (8mL), and trifluoroacetic acid (0.8mL) is added in the reaction mixture.Stir this mixture, till raw material disappears.Vacuum is removed excessive trifluoroacetic acid, obtains crude product.MS(M+1)：368.5。Then this salt is neutralized with MP carbonate: 1.5g MP carbonate is added in the solution of above-mentioned salt in MeOH (6mL) and with this mixture stirred 1 hour, filter then and concentrate.
Step C:5-butyryl radicals-2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201112
With sodium triacetoxy borohydride (51mg; 0.24mmol) add to 5-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles (59mg, 0.16mmol) and cyclobutanone (24 μ L are 0.32mmol) in the mixture in methylene dichloride (2mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (34.5mg) of required product.MS(M+1)：422.0。 1H?NMR(600MHz，CDCl 3)δppm?0.96(d，J＝6.66Hz，3H)，1.02-1.18(m，1H)，1.15-1.32(m，1H)，1.07(t，J＝7.30Hz，3H)，1.51-1.72(m，2H)，1.73-1.90(m，4H)，1.96(q，J＝9.81Hz，1H)，2.75-2.39(m，2H)，2.47-2.67(m，2H)，2.75-3.04(m，4H)，3.11-3.22(m，1H)，3.24-3.39(m，1H)，3.42-3.55(m，1H)，3.56-3.76(m，3H)，3.81-3.93(m，1H)，4.52-4.71(m，2H)，7.23-7.32(m，1H)，7.38(s，1H)，7.82(d，J＝8.19Hz，1H)。
Embodiment 114.5-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
With sodium triacetoxy borohydride (70mg; 0.33mmol) add to 5-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles (80mg, 0.22mmol) and tetrahydrochysene-4H-pyrans-4-ketone (40 μ L are 0.43mmol) in the mixture in methylene dichloride (3mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (40mg) of required product.MS(M+1)：452.0。 1H?NMR(600MHz，CDCl 3)δppm?0.98(d，J＝6.40Hz，3H)，1.06-1.15(m，1H)，1.08(t，J＝7.42Hz，3H)，1.81-1.31(m，1H)，1.55-1.73(m，2H)，1.74-1.84(m，1H)，1.85-1.90(m，2H)，1.95-2.15(m，2H)，2.44-2.91(m，6H)，2.96(t，J＝7.17Hz，2H)，2.93-3.11(m，1H)，3.24-3.39(m，1H)，3.45(t，J＝11.65Hz，3H)，3.76-3.88(m，1H)，4.10-4.28(m，1H)，4.15(dd，J＝11.65，3.71Hz，2H)，4.53-4.74(m，2H)，7.34(d，J＝8.70Hz，1H)，7.45(s，1H)，7.88(d，J＝8.70Hz，1H)。
Embodiment 115.2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201122
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
In room temperature, to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester (100mg, 0.25mmol) in the solution in methyl alcohol (1mL), add the solution of HCl in ether (2M, 3mL).Stir this mixture, till not observing any raw material, concentrating under reduced pressure then.Then this salt is neutralized with MP carbonate: 0.51g MP carbonate is added in the MeOH solution (2mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.
Step B:2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201132
With sodium triacetoxy borohydride (15mg 0.24mmol) adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (50mg, 0.17mmol) and cyclopentanone (30 μ L are 0.34mmol) in the mixture in methylene dichloride (2mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (15mg) of required product.MS(M+1)：366.0。 1HNMR(400MHz，CDCl 3)δppm?0.95(d，J＝6.44Hz，3H)，0.99-1.35(m，2H)，1.44-2.22(m，12H)，2.57-3.17(m，4H)，2.83(d，J＝15.82Hz，1H)，3.44-3.72(m，3H)，3.90(d，J＝15.82Hz，1H)，4.15-4.36(m，1H)，4.52-4.70(m，1H)，6.89-7.23(m，3H)。
Embodiment 116.2-cyclopentyl-5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201141
Steps A: carbonyl 5-methyl-8-[(4-methyl piperidine-1-yl)]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201142
Under room temperature and nitrogen atmosphere, with 60%NaH (74mg 1.85mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (200mg is 0.503mmol) in the suspension in DMF (5mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, room temperature add methyl iodide (62 μ L, 0.99mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, resistates is dissolved in methylene dichloride, washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：412.1。
Step B:5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
In room temperature, to thick 5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, in the mixture of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester in MeOH (3mL), add the solution of saturated HCl in ether (2M, 2mL).Stir this mixture, till raw material disappears.Removing desolvates obtains the hydrochloride form of required product.MS(M+1)：312.3。
Step C:2-cyclopentyl-5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201151
With sodium triacetoxy borohydride (136mg, 0.64mmol) add to 5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (133mg, 0.35mmol) and cyclopentanone (76 μ L are 0.86mmol) in the mixture in methylene dichloride (3mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.Crude product is by preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (46.6mg) of required product.MS(M+1)：380.0。 1H?NMR(600MHz，CDCl 3)d?ppm?0.98(d，J＝6.40Hz，3H)，1.56-1.71(m，4H)，1.84-1.94(m，2H)，2.01-2.17(m，5H)，2.93-3.18(m，6H)，3.36-3.46(m，2H)，3.53-3.63(m，1H)，3.66(s，3H)，3.72-3.85(m，1H)，3.93(dd，J＝11.14，4.99Hz，1H)，4.17(d，J＝14.34Hz，1H)，4.74(d，J＝14.34Hz，1H)，7.13-7.38(m，2H)，7.47(s，1H)。
Embodiment 117.5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201152
With sodium triacetoxy borohydride (85mg, 0.40mmol) add to 5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (80mg, 0.25mmol) and tetrahydrochysene-4H-pyrans-4-ketone (47 μ L are 0.51mmol) in the mixture in methylene dichloride (3mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (20mg) of required product.MS(M+1)：396.0。 1H?NMR(600MHz，CDCl 3)δppm?0.97(d，J＝6.14Hz，3H)，1.17-1.31(m，1H)，1.58-1.81(m，2H)，1.91-2.15(m，6H)，2.98(d，J＝12.29Hz，2H)，3.30-3.51(m，4H)，3.59-3.81(m，3H)，3.63(s，3H)，3.84-3.93(m，1H)，4.13(d，J＝11.01Hz，2H)，4.24(d，J＝14.34Hz，1H)，4.51-4.72(m，2H)，7.21(d，J＝7.42Hz，2H)，7.40-7.44(m，1H)。
Embodiment 118.2-cyclopentyl-5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201161
Steps A: carbonyl 5-ethyl-8-[(4-methyl piperidine-1-yl)]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201162
Under room temperature and nitrogen atmosphere, with 60%NaH (60mg 1.50mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (160mg is 0.40mmol) in the suspension in DMF (2mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, agent such as iodoethane (64 μ L, 0.80mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：426.1。
Step B:5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201163
In room temperature, to thick 5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, add in the mixture of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester in MeOH (2mL) solution of saturated HCl in ether (2M, 2mL).Stir this mixture, till raw material disappears.Remove and desolvate, obtain the hydrochloride form of required product.Then this salt is neutralized with MP carbonate: 0.6g MP carbonate is added in the MeOH solution (2mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.MS(M+1)：326.3。
Step C:2-cyclopentyl-5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
With sodium triacetoxy borohydride (120mg 0.57mmol) adds to 5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, (71 μ L are 0.95mmol) in the mixture in methylene dichloride (3mL) for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and cyclopentanone.With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain two tfa salts of required product, it is yellow solid (101mg, three steps 64%).MS(M+1)：394.0。 1H?NMR(400MHz，CDCl 3)δppm?0.98(d，J＝6.44Hz，3H)，1.05-1.28(m，2H)，1.34(t，J＝7.23Hz，3H)，1.56-1.80(m，5H)，1.81-1.97(m，2H)，1.98-2.22(m，4H)，2.76-2.92(m，1H)，2.99(d，J＝16.21Hz，1H)，3.31-3.48(m，2H)，3.52-3.68(m，1H)，3.86-4.02(m，2H)，4.03-4.23(m，2H)，4.17(d，J＝13.70Hz，1H)，4.74(d，J＝13.70Hz，1H)，4.80-5.02(m，3H)，7.23(d，J＝8.40Hz，1H)，7.30(d，J＝8.40Hz，1H)，7.48(s，1H)。
Embodiment 119.5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201172
According to the method that is similar to embodiment 118 step C, by 5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and tetrahydrochysene-4H-pyrans-4-ketone, the tfa salt of preparation title compound.MS(M+1)：410.0。 1H?NMR(600MHz，CD 3OD)δppm0.83-0.91(m，3H)，0.95-1.16(m，2H)，1.18-1.27(m，3H)，1.33-1.40(m，2H)，1.42-1.75(m，3H)，1.81(q，J＝11.35Hz，1H)，2.02-2.12(m，1H)，2.68-2.84(m，1H)，2.92-3.06(m，1H)，3.09-3.23(m，3H)，3.28-3.51(m，1H)，3.39(t，J＝11.52Hz，1H)，3.64-3.77(m，1H)，3.55-3.64(m，1H)，3.64-3.77(m，1H)，3.83(d，J＝10.24Hz，0.5H)，3.87-3.97(m，0.5H)，4.01(d，J＝11.52Hz，1H)，4.06-4.16(m，2H)，4.21(d，J＝14.34Hz，0.5H)，4.32-4.42(m，0.5H)，4.43-4.55(m，1H)，4.55-4.67(m，0.5H)，4.63(d，J＝14.34Hz，0.5H)，7.13(d，J＝8.19Hz，1H)，7.39(d，J＝8.19Hz，1H)，7.45(d，J＝12.80Hz，1H)。
Embodiment 120.2-cyclopentyl-5-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201181
Steps A: 5-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201182
Under room temperature and nitrogen atmosphere, with 60%NaH (60mg 1.50mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (160mg is 0.40mmol) in the suspension in DMF (2mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, room temperature add (chloromethyl) cyclopropane (78 μ L, 0.84mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：452.1。
Step B:5-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201191
In room temperature, to thick 5-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, add in the mixture of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester in MeOH (2mL) solution of saturated HCl in ether (2M, 2mL).Stir this mixture, till raw material disappears.Removing desolvates obtains the hydrochloride form of required product.MS(M+1)：352.36。Then this salt is neutralized with MP carbonate: 0.62g MP carbonate is added in the MeOH solution (2mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.
Step C:2-cyclopentyl-5-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201192
With sodium triacetoxy borohydride (120mg 0.57mmol) adds to 5-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, (71 μ L are 0.80mmol) in the mixture in methylene dichloride (3mL) for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and cyclopentanone.With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain two tfa salts of required product, it is yellow solid (171mg, three steps 66%).MS(M+1)：420.15。 1H?NMR(400MHz，CDCl 3)δppm?0.29(m，2H)，0.53-0.63(m，2H)，0.98(d，J＝6.44Hz，3H)，1.05-1.19(m，1H)，1.58-1.73(m，4H)，1.84-1.94(m，2H)，2.01-2.18(m，6H)，2.94-3.07(m，1H)，3.34-3.52(m，3H)，3.54-3.66(m，1H)，3.85-4.04(m，4H，)4.17(d，J＝14.84Hz，1H)，4.73(d，J＝14.84Hz，1H)，7.23(d，J＝8.40Hz，1H)，7.32(d，J＝8.40Hz，1H)，7.46(s，1H)。
Embodiment 121.5-(cyclobutylmethyl)-2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201201
Steps A: 5-(cyclobutylmethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Under room temperature and nitrogen atmosphere, with 60%NaH (60mg 1.50mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (160mg is 0.40mmol) in the suspension in DMF (2mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, room temperature add (brooethyl) tetramethylene (80 μ L, 0.71mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：466.1。
Step B:5-(cyclobutylmethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201203
In room temperature, to thick 5-(cyclobutylmethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, add in the mixture of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester in MeOH (2mL) solution of saturated HCl in ether (2M, 2mL).Stir this mixture, till raw material disappears.Remove and desolvate, obtain the hydrochloride form of required product.MS(M+1)：366.38。Then this salt is neutralized with MP carbonate: 0.75g MP carbonate is added in the MeOH solution (3mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.
Step C:5-(cyclobutylmethyl)-2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201211
With sodium triacetoxy borohydride (120mg 0.57mmol) adds to 5-(cyclobutylmethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, (71 μ L are 0.80mmol) in the mixture in methylene dichloride (3mL) for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and cyclopentanone.With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (128mg, three steps 48%) of required product.MS(M+1)：434.2。 1H?NMR(400MHz，CDCl 3)δppm?0.98(d，J＝6.25Hz，3H)，1.59-1.93(m，12H)，1.93-2.24(m，7H)，2.67-2.78(m，1H)，2.94-3.08(m，1H)，3.31-3.50(m，3H)，3.54-3.68(m，1H)，3.90-4.11(m，3H)，4.17(d，J＝14.65Hz，1H)，4.74(d，J＝14.65Hz，1H)，7.21(d，J＝8.20Hz，1H)，7.31(d，J＝8.20Hz，1H)，7.48(s，1H)。
Embodiment 122.2-cyclopentyl-5-[(5-methyl is different
Figure BSA00000321451201212
Azoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201213
Steps A: the 5-[(5-methyl is different
Figure BSA00000321451201214
Azoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201221
Under room temperature and nitrogen atmosphere, with 60%NaH (74mg 1.85mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (200mg is 0.503mmol) in the suspension in DMF (6mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, and adding 4-(chloromethyl)-5-methyl is different
Figure BSA00000321451201222
Azoles (87mg, 0.66mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：493.1。
Step B:5-[(5-methyl is different Azoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201224
In room temperature, different to the 5-[(5-methyl
Figure BSA00000321451201225
Azoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, in the mixture of 5-tetrahydrochysene-2H-pyrido [4,3-b] Indoline-2-carboxylic acid tert-butyl ester crude product in MeOH (2mL), add the solution of saturated HCl in ether (2M, 2mL).Stir this mixture, till raw material disappears.Removing desolvates obtains the hydrochloride form of required product.MS(M+1)：393.1。Then this salt is neutralized with MP carbonate: 0.75g MP carbonate is added in the MeOH solution (3mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.
Step C:2-cyclopentyl-5-[(5-methyl is different Azoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201231
(180mg, it is different 0.85mmol) to add to the 5-[(5-methyl with sodium triacetoxy borohydride
Figure BSA00000321451201232
Azoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, (90 μ L are 1.02mmol) in the mixture in methylene dichloride (3mL) for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and cyclopentanone.With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (20mg, three steps 6%) of required product.MS(M+1)：461.1。 1H?NMR(400MHz，CDCl 3)δppm?0.97(d，J＝6.25Hz，3H)，1.03-1.34(m，2H)，1.53-2.22(m，10H)，2.29(m，3H)，2.72-3.08(m，1H)，3.04(d，J＝13.47Hz，1H)，3.24-3.51(m，2H)，3.24-3.51(m，2H)，3.53-3.66(m，1H)，3.67-3.85(m，1H)，3.85-3.98(m，1H)，4.10(d，J＝13.47Hz，1H)，4.55-4.78(m，2H)，5.10-5.30(m，2H)，5.65(s，1H)，7.20(d，J＝8.20Hz，1H)，7.31(d，J＝8.20Hz，1H)，7.45(s，1H)。
Embodiment 123.2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-the 5-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201233
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-the 5-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201241
Under room temperature and nitrogen atmosphere, with 60%NaH (74mg 1.85mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (200mg is 0.503mmol) in the suspension in DMF (7mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, adds 4-(chloromethyl)-2-methyl isophthalic acid in room temperature, the 3-thiazole (120mg, 0.81mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, resistates are dissolved in methylene dichloride and wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：509.1。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-the 5-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201242
In room temperature, to thick 8-[(4-methyl piperidine-1-yl) carbonyl]-the 5-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] in the mixture of the Indoline-2-carboxylic acid tert-butyl ester in MeOH (2mL), add the solution of saturated HCl in ether (2M, 3mL).Stir this mixture, till raw material disappears.Remove and desolvate, obtain the hydrochloride form of required product.MS(M+1)：409.1。Then this salt is neutralized with MP carbonate: 0.75g MP carbonate is added in the MeOH solution (3mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.
Step C:2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-the 5-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201251
With sodium triacetoxy borohydride (180mg, 0.85mmol) add to 8-[(4-methyl piperidine-1-yl) carbonyl]-the 5-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methyl]-2,3,4, (90 μ L are 1.02mmol) in the mixture in methylene dichloride (3mL) for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and cyclopentanone.With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.Crude product is by preparation HPLC (5-75%CH 3CN) carry out purifying, follow recrystallization, obtain the tfa salt of required product, it is yellow solid (224mg, three steps 63%).MS(M+1)：477.0。 1H?NMR(400MHz，CDCl 3)δppm?0.99(d，J＝6.25Hz，3H)，1.48-1.91(m，12H)，1.96-2.10(m，2H)，2.70(s，3H)，2.79-3.02(m，8H)，3.80(s，2H)，5.31(d，J＝0.98Hz，2H)，6.37(s，1H)，7.16-7.20(m，1H)，7.21-7.29(m，1H)，7.54(s，1H)。
Embodiment 124.2-{2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide
Figure BSA00000321451201252
Steps A: 5-[2-(dimethylamino)-2-oxoethyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201253
Under room temperature and nitrogen atmosphere, with 60%NaH (87mg 2.17mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (400mg is 1mmol) in the suspension in DMF (10mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, add 2-chloro-N,N-dimethylacetamide (180 μ L, 1.75mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, resistates are dissolved in methylene dichloride and wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：483.2。
Step B:N, N-dimethyl-2-{8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } ethanamide
Figure BSA00000321451201261
According to the method that is similar to embodiment 123 step B, by 5-[2-(dimethylamino)-2-oxoethyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester, preparation title compound.MS(M+1)：383.4。
Step C:2-{2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide
Figure BSA00000321451201262
With sodium triacetoxy borohydride (86mg, 0.40mmol) add to N, N-dimethyl-2-{8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } ethanamide (103mg, 0.27mmol) and cyclobutanone (40 μ L are 0.53mmol) in the mixture in methylene dichloride (2mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt of required product, it is yellow solid (50mg, 28%).MS(M+1)：437.0。 1H?NMR(400MHz，CDCl 3)δppm?0.94(d，J＝6.44Hz，10H)，0.98-1.30(m，2H)，1.46-1.84(m，4H)，1.84-1.99(m，1H)，2.36-2.61(m，2H)，2.71-3.18(m，2H)，2.93(s，3H)，3.13(s，3H)，3.47-3.77(m，3H)，2.29(d，J＝7.23Hz，5H)，4.10-4.37(m，1H)，3.69(d，J＝14.45Hz，4H)，4.66(d，J＝17.18Hz，1H)，4.88(d，J＝17.38Hz，1H)，4.53-7.43(m，1H)，7.04-7.31(m，3H)。
Embodiment 125.2-{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide
Figure BSA00000321451201271
With sodium triacetoxy borohydride (86mg, 0.40mmol) add to N, N-dimethyl-2-{8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } ethanamide (103mg, 0.27mmol) and cyclopentanone (46 μ L are 0.52mmol) in the mixture in methylene dichloride (4mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt of required product, it is white solid (49mg, 27%).MS(M+1)：451.0。 1H?NMR(400MHz，CDCl 3)δppm?0.94(d，J＝6.30Hz，3H)，1.01-1.27(m，2H)，1.48-2.19(m，11H)，2.73-2.99(m，8H)，3.09-3.27(m，4H)，3.50(t，J＝5.9Hz，1H)，3.61-3.77(m，1H)，3.89-4.02(m，1H)，4.31-4.49(m，1H)，4.51-4.75(m，1H)，4.65(d，J＝17.38Hz，1H)，4.84(d，J＝17.38Hz，1H)，6.39-6.61(m，1H)，7.11(s，1H)，7.29(s，1H)。
Embodiment 126.2-{2-cyclohexyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide
Figure BSA00000321451201272
With sodium triacetoxy borohydride (86mg, 0.40mmol) add to N, N-dimethyl-2-{8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } ethanamide (103mg, 0.27mmol) and pimelinketone (56 μ L are 0.54mmol) in the mixture in methylene dichloride (4mL).With this mixture in stirred overnight at room temperature.Add once more sodium triacetoxy borohydride (60mg, 0.28mmol) and pimelinketone (30 μ L, 0.29mmol) and stir this mixture, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt of required product, it is faint yellow solid (49.7mg, 27%).MS(MS+1)：465.0。 1H?NMR(600MHz，CDCl 3)δppm?0.96(d，J＝6.40Hz，3H)，1.14-1.29(m，2H)，1.31-1.45(m，2H)，1.51-1.70(m，4H)，1.75(d，J＝13.06Hz，1H)，1.97(d，J＝13.57Hz，2H)，2.18(t，J＝12.42Hz，2H)，2.85-2.93(m，1H)，2.97(s，3H)，3.13(s，3H)，3.21-3.44(m，9H)，3.76(d，J＝7.94Hz，1H)，4.18(d，J＝13.82Hz，1H)，4.59-4.72(m，1H)，4.68(d，J＝17.41Hz，1H)，4.91(d，J＝17.41Hz，1H)，7.14(d，J＝12.00Hz，1H)，7.18(d，J＝12Hz，1H)，7.38(s，1H)。
Embodiment 127.{2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate
Figure BSA00000321451201281
Steps A: 5-(2-oxyethyl group-2-oxoethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201282
Under room temperature and nitrogen atmosphere, with 60%NaH (28mg 0.7mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (200mg is 0.50mmol) in the suspension in DMF (7mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, add ethyl bromoacetate (0.1mL, 0.58mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, resistates is dissolved in methylene dichloride, washes with water, uses dried over sodium sulfate.Removing desolvates obtains required product.MS(M+1)：484.2。
Step B:{8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } preparation of ethyl acetate
In room temperature, to thick 5-(2-oxyethyl group-2-oxoethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, add in the mixture of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester in MeOH (2mL) solution of saturated HCl in ether (2M, 2mL).Stir this mixture, till raw material disappears.The hydrochloride form that removing desolvates obtains required product (in the reaction, ethyl and MeOH exchange obtain methyl ester).MS(M+1)：370.1。Then this salt is neutralized with MP carbonate: 0.75g MP carbonate is added in the MeOH solution (3mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.
Step C:{2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } preparation of methyl acetate
Figure BSA00000321451201292
With sodium triacetoxy borohydride (46mg, 0.22mmol) add to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl ethyl acetate (53mg, 0.14mmol) and cyclobutanone (21 μ L are 0.28mmol) in the mixture in anhydrous methylene chloride (2mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain two tfa salts of required product, it is yellow solid (19.6mg, 22%).MS(MS+1)：424.0。 1H?NMR(400MHz，CDCl 3)δppm?0.97(d，J＝6.44Hz，3H)，1.03-1.31(m，2H)，1.47-1.89(m，4H)，1.86-2.04(m，1H)，2.22-2.38(m，2H)，2.47-2.67(m，2H)，2.72-3.10(m，3H)，3.14-3.34(m，2H)，3.56-3.82(m，3H)，3.74(s，3H)，3.87(d，J＝14.65Hz，1H)，4.44-4.86(m，4H)，7.16-7.27(m，2H)，7.38(bs，1H)。
Embodiment 128.{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate
Figure BSA00000321451201301
With sodium triacetoxy borohydride (46mg, 0.22mmol) add to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl ethyl acetate (53mg, 0.14mmol) and cyclopentanone (25 μ L are 0.28mmol) in the mixture in anhydrous methylene chloride (2mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.Crude product obtains the tfa salt of required product by reversed-phase HPLC (5-75%CH3CN) purifying, and it is white solid (22mg, 24%).MS(M+1)：438.0。 1H?NMR(400MHz，CDCl 3)δppm?0.96(d，J＝6.25Hz，3H)，1.02-1.31(m，2H)，1.52-2.21(m，13H)，2.71-3.08(m，3H)，3.19-3.42(m，2H)，3.48-3.64(m，1H)，3.74(s，3H)，3.80-3.94(m，1H)，4.09(d，J＝13.28Hz，1H)，4.48-4.87(m，3H)，7.20(s，2H)，7.41(s，1H)。
Embodiment 129.{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } acetate
Figure BSA00000321451201302
To 2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate (deriving from the above-mentioned 5-of 0.2g (2-oxyethyl group-2-oxoethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester) adds MeOH/H in the solution 2O/THF (each 3mL) and NaOH (96mg, mixture 0.24mmol), and with this mixture in stirring at room.Under reduced pressure remove then and desolvate, and the pH of resistates is adjusted to 5.Reclaim formed throw out.The latter is by reversed-phase HPLC (5-75%CH 3CN) carry out purifying, obtain yellow solid (24mg, four steps 7.3%).MS(M+1)：424.0。 1H?NMR(600MHz，CDCl 3)δppm?0.94(bs，3H)，1.11-1.22(m，1H)，1.23-1.42(m，2H)，1.54-2.10(m，9H)，2.13-2.31(m，2H)，2.55-2.62(m，1H)，2.74-2.97(m，2H)，2.98-3.30(m，3H)，3.53-3.66(m，1H)，3.68-3.87(m，2H)，3.94-4.15(m，1H)，4.56-4.84(m，2H)，7.01-7.28(m，2H)，8.21(m，1H)，11.06-11.18(m，1H)。
Embodiment 130.{2-cyclohexyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate
Figure BSA00000321451201311
With sodium triacetoxy borohydride (80mg, 0.38mmol) add to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl ethyl acetate (93mg, 0.24mmol) and pimelinketone (60 μ L are 0.58mmol) in the mixture in anhydrous methylene chloride (3mL).With this mixture in stirring at room.Add once more sodium triacetoxy borohydride (60mg, 0.28mmol) and pimelinketone (30 μ L, 0.29mmol), but transform still incomplete, still remaining about 20% raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.Crude product obtains the tfa salt of required product by reversed-phase HPLC (5-75%CH3CN) purifying, and it is white solid (18mg, 11%).MS(M+1)：452.0。 1H?NMR(600MHz，CDCl 3)δppm?0.97(d，J＝6.40Hz，3H)，1.03-1.32(m，3H)，1.33-1.46(m，2H)，1.52-1.70(m，4H)，1.75(d，J＝9.73Hz，2H)，1.97(d，J＝12.80Hz，2H)，2.14-2.25(m，2H)，2.75-3.08(m，3H)，3.34-3.47(m，2H)，3.73(m，3H)，3.79-3.89(m，1H)，4.23(d，J＝13.82Hz，1H)4.45-4.84(m，3H)5.08-5.40(m，3H)，7.22(m，2H)，7.44(m，1H)。
Embodiment 131.5-(2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl)-the 2-methylfuroate
Under room temperature and nitrogen atmosphere, with 60%NaH (17mg 0.42mmol) whole part adds to 2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, in the suspension of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles crude product in DMF (3mL).This mixture was stirred 30 minutes, add 5-(chloromethyl)-2-ethyl furoate (66 μ L, 0.43mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, resistates are dissolved in methylene dichloride and wash with water, use dried over sodium sulfate, then concentrating under reduced pressure.This crude product is by reversed-phase HPLC (5-75%CH 3CN) purifying obtains required compound, and it is a white solid, that is its two-tfa salt (97.86mg, four steps 17%).MS(M+1)：518.0。 1H?NMR(400MHz，CDCl 3)δppm?0.95(d，J＝6.25Hz，3H)，0.99-1.26(m，2H)，1.30(t，J＝7.13Hz，3H)，1.48-2.08(m，9H)，2.09-2.22(m，2H)，2.67-3.04(m，2H)，3.05-3.20(m，1H)，3.23-3.43(m，2H)，3.54-3.78(m，2H)，3.82-3.94(m，1H)，4.11(d，J＝14.06Hz，1H)，4.27(q，J＝7.03Hz，2H)，4.50-4.72(m，2H)，5.18(s，2H)，6.16(s，1H)，7.00(d，J＝3.40Hz，1H)，7.12-7.20(m，1H)，7.24-7.30(m，1H)，7.37(bs，1H)。
Embodiment 132.5-(2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl)-the 2-furancarboxylic acid
Figure BSA00000321451201322
To 5-({ 2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl)-(33mg is 0.04mmol) in MeOH/THF/H for the 2-methylfuroate 2Add NaOH (17mg 0.42mmol) in the solution in O (each 1mL) mixture, and with this mixture in stirred overnight at room temperature.Remove then and desolvate, and the pH of resistates is adjusted to 5.Collecting precipitation is then by reversed-phase HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (8mg, 25%) of required compound.MS(MS+1)：490.0。
Embodiment 133.2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201331
The preparation of steps A: 1-(chloromethyl)-4-(methylthio group) benzene
Figure BSA00000321451201332
To 4-(methylthio group) benzylalcohol (1g, 6.48mmol) thionyl chloride (0.2mL) in the solution in anhydrous methylene chloride (2mL), and with this mixture stirring at room 2 hours, concentrate then.This muriate (0.6g, 54%) need not to be further purified and can use. 1H?NMR(400MHz，CDCl 3)δppm2.49(s，3H)4.57(s，2H)7.22-7.28(m，2H)7.29-7.36(m，2H)。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Under room temperature and nitrogen atmosphere, with 60%NaH (74mg 1.85mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (200mg is 0.50mmol) in the suspension in DMF (7mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, room temperature add 1-(chloromethyl)-4-(methylthio group) benzene (100mg, 0.58mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：534.13。
Step C:8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
In room temperature, to 8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-1,3,4, add in the mixture of 5-tetrahydrochysene-2H-pyrido [4,3-b] Indoline-2-carboxylic acid tert-butyl ester crude product in MeOH (2mL) solution of saturated HCl in ether (2M, 2mL).Stir this mixture, till raw material disappears.Remove and desolvate, obtain required product 8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4, the hydrochloride form of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.MS(M+1)：434.09。Then this salt is neutralized with MP carbonate: 0.76g MP carbonate is added in the MeOH solution (3mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.
Step D:2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201342
With sodium triacetoxy borohydride (128mg, 0.604mmol) add to 8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (89 μ L are 1.01mmol) in the mixture in anhydrous methylene chloride (3mL) for indoles and cyclopentanone.With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain two tfa salts (43mg, three steps 14%) of required product.MS(M+1)：502.15。 1H?NMR(400MHz，CDCl 3)δppm?0.96(d，J＝6.25Hz，3H)，1.52-2.21(m，11H)，2.89(s，3H)，2.84(d，J＝12.89Hz，2H)，3.21-3.36(m，2H)，3.50-3.62(m，1H)，3.67-3.90(m，2H)，4.14(d，J＝13.86Hz，1H)，4.52-4.76(m，2H)，5.08-5.23(m，2H)，6.83(d，J＝8.20Hz，2H)，7.12(d，J＝8.20Hz，2H)，7.08-7.22(m，2H)，7.46(s，1H)。
Embodiment 134.2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles 2-oxide compound
Figure BSA00000321451201351
To 2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (12mg, 0.019mmol) add oxone (oxone) (54mg) in the solution in MeOH (2mL), and with this mixture in stirred overnight at room temperature.Then this mixture is filtered and concentrating under reduced pressure, then by reversed-phase HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (4mg) of title compound.MS(M+1)：550.1。 1H?NMR(400MHz，CDCl 3)δppm?0.98(d，J＝6.25Hz，3H)，1.56-2.19(m，11H)，2.36-2.59(m，1H)，3.05(s，3H)，3.14-3.67(m，10H)，3.92(t，J＝9.57Hz，1H)，4.00(d，J＝14.65Hz，1H)，4.82-5.05(m，2H)，6.51(d，J＝8.59Hz，1H)，7.34(d，J＝8.20Hz，2H)，7.54(dd，J＝8.49，1.66Hz，1H)，7.72(s，1H)，7.88(d，J＝8.20Hz，2H)。
Embodiment 135.2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methyl sulphonyl) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201361
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-5-[4-(methyl sulphonyl) benzyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201362
Under room temperature and nitrogen atmosphere, with 60%NaH (74mg 1.85mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (200mg is 0.503mmol) in the suspension in DMF (7mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, room temperature add 1-(chloromethyl)-4-(methyl sulphonyl) benzene (123mg, 0.60mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：566.48。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methyl sulphonyl) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201363
With thick 8-[(4-methyl piperidine-1-yl) carbonyl]-the 5-[4-ethylsulfonyl) benzyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester is dissolved in methylene dichloride (3mL), and trifluoroacetic acid (1mL) is added in the reaction mixture.Stir this mixture, till raw material disappears.Vacuum is removed excessive trifluoroacetic acid, obtains thick 8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methyl sulphonyl) benzyl]-2,3,4, the trifluoroacetic acid salt form of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.Then this salt is neutralized with MP carbonate: 0.75g MP carbonate is added in the MeOH solution (3mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate.MS(M+1)：466.4。
Step C:2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methyl sulphonyl) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201371
With sodium triacetoxy borohydride (80mg; 0.38mmol) add to half 8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methyl sulphonyl) benzyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] (50 μ L are 56mmol) in the mixture in methylene dichloride (2mL) for indoles crude product and cyclopentanone.With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.By preparation HPLC (5-75%CH 3CN) carry out purifying, obtain two tfa salts of required product, it is faint yellow solid (40mg, three steps 10%).MS(M+1)：534.0。 1H?NMR(600MHz，CDCl 3)δppm?1.07(d，J＝6.40Hz，3H)，1.17-1.40(m，2H)，1.63-2.06(m，8H)，2.06-2.38(m，4H)，2.96(d，J＝18.18Hz，2H)，3.09(s，3H)，3.32-3.52(m，2H)，3.64-3.78(m，1H)，3.89(bs，1H)，3.99-4.09(m，1H)，4.25(d，J＝13.82Hz，1H)，4.76(bs，1H)，4.86(d，J＝13.31Hz，1H)，5.42(q，J＝17.6Hz，2H)，7.15(d，J＝7.94Hz，2H)，7.20-7.32(m，1H)，7.35(bs，1H)，7.62(s，1H)，7.90(d，J＝7.94Hz，2H)。
Embodiment 136.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201381
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-5-(4-nitrophenyl)-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201382
Under room temperature and nitrogen atmosphere, with 60%NaH (70mg 1.75mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (200mg is 0.503mmol) in the suspension in DMF (5mL) for the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, add 1-fluoro-4-oil of mirbane (70 μ L, 0.66mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：519.5。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
With 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester is dissolved in methylene dichloride (5mL), and trifluoroacetic acid (0.5mL) is added in the reaction mixture.Stir this mixture, till raw material disappears.Vacuum is removed excessive trifluoroacetic acid, obtains the trifluoroacetic acid salt form of crude product.Then this salt is neutralized with MP carbonate: 0.75g MP carbonate is added in the MeOH solution (3mL) of above-mentioned salt, and this mixture was stirred 1 hour, filter then and concentrate (0.4g).MS(M+1)：419.4。
Step C:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201391
With sodium triacetoxy borohydride (80mg, 0.38mmol) add to 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (80mg, 0.19mmol) and tetrahydrochysene-4H-pyrans-4-ketone (35 μ L are 0.38mmol) in the mixture in methylene dichloride (4mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.Crude product carries out purifying (5-75%) by preparation HPLC, obtains the tfa salt (18mg, 14%) of required product.MS(M+1)：503.5。 1H?NMR(600MHz，CDCl 3)：δppm?0.98(d，J＝6.40Hz，3H)，1.05-1.31(m，2H)，1.51(t，J＝6.91Hz，1H)，1.56-1.86(m，3H)，1.95-2.18(m，4H)，2.73-2.92(m，2H)，2.97-3.11(m，1H)，3.53-3.39(m，1H)，3.48(t，J＝11.65Hz，2H)，3.53-3.65(m，1H)，3.68-3.82(m，2H)，3.83-3.95(m，1H)，4.16(d，J＝9.22Hz，2H)，4.60-4.77(m，2H)，7.20-7.33(m，2H)，7.51-7.63(m，3H)，8.43(d，J＝8.19Hz，2H)。
Embodiment 137.{4-[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] phenyl } amine
Figure BSA00000321451201401
To 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (170mg 0.24mmol) adds Pd/C in the solution in MeOH (8mL), and this mixture is placed H indoles 2TFA 2(30psi) in stirred overnight at room temperature.Then this mixture is filtered and concentrating under reduced pressure, by reversed-phase HPLC (5-75%CH 3CN) carry out purifying, obtain the tfa salt (153mg, 94%) of required compound.MS(M+1)：474.36。 1H?NMR(400MHz，CD 3OD)δppm?0.84-0.92(m，1H)，0.88(d，J＝6.45Hz，3H)，0.95-1.19(m，3H)，1.41-1.74(m，3H)，1.76-1.91(m，1H)，2.08(d，J＝12.11Hz，2H)，2.66-3.12(m，4H)，3.35-3.53(m，1H)，3.41(t，J＝11.32Hz，2H)，3.57-3.94(m，2H)，4.03(dd，J＝11.62，4.00Hz，2H)，4.40-4.57(m，1H)，4.63-4.79(m，2H)，6.95-7.03(m，2H)，7.08-7.18(m，4H)，7.54-7.5(m，1H)。
Embodiment 138.N-{4-[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] phenyl } ethanamide
Figure BSA00000321451201402
Will 4-[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] phenyl } amine (33mg, 0.05mmol) be dissolved in diacetyl oxide (0.5mL) and pyridine (0.5mL), and with this mixture in stirring at room, till not observing any raw material.With this mixture concentrating under reduced pressure,, and use NaHCO then with the methylene dichloride dilution 3, water and saturated NaCl solution washing.After drying and the concentrating under reduced pressure, crude product obtains the tfa salt (11.62mg, 34%) of required compound by reversed-phase HPLC (5-75%) purifying.MS(M+1)：515.5。 1H?NMR(600MHz，CDCl 3)δppm?0.97(d，J＝6.14Hz，3H)，0.79-1.37(m，4H)，1.45-1.89(m，3H)，1.92-2.34(m，7H)，2.59-2.71(m，1H)，2.76-2.92(m，1H)，2.93-3.07(m，1H)，3.08-3.28(m，2H)，3.42-3.56(m，2H)，3.61-3.83(m，3H)，4.09-4.22(m，2H)，4.28(d，J＝12.54Hz，1H)，4.57-4.80(m，2H)，5.88-6.27(m，3H)，6.86-7.10(m，4H)，7.42-7.72(m，3H)。
Embodiment 139.4-{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } phenyl) amine
Figure BSA00000321451201411
Steps A: 2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201412
With sodium triacetoxy borohydride (81mg, 0.38mmol) add to 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (80mg, 0.19mmol) and cyclopentanone (34 μ L are 0.38mmol) in the mixture in methylene dichloride (3mL).With this mixture in stirring at room, till not observing any raw material.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.MS(M+1)：487.5。
Step B:4-{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } phenyl) preparation of amine
Figure BSA00000321451201421
To above-mentioned 2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2,3,4, add Pd/C in the solution of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles in MeOH (6mL), and this mixture is placed H 2(30psi) in stirred overnight at room temperature.Then this mixture is filtered and concentrating under reduced pressure,, obtain the tfa salt (15.69mg, two ones 12%) of required compound by reversed-phase HPLC (5-75%) purifying.MS(M+1)：457.48。 1H?NMR(600MHz，CD 3OD)δppm?0.83(d，J＝6.70Hz，3H)，0.94-1.16(m，2H)，1.42-1.52(m，1H)，1.52-1.84(m，9H)，2.10-2.26(m，2H)，2.68-2.80(m，1H)，2.80-2.90(m，1H)，2.90-3.10(m，2H，)3.33-3.45(m，1H)，3.62-3.76(m，2H)，3.77-3.90(m，1H)，4.34(d，J＝14.08Hz，1H)，4.43-4.54(m，1H)，4.73(d，J＝14.59Hz，1H)，7.10(s，2H)，7.17(d，J＝8.70Hz，2H)，7.26(d，J＝8.45Hz，2H)，7.53(s，1H)。
Embodiment 140.2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201422
Steps A: 2-sec.-propyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid
Figure BSA00000321451201423
(5g, 32mmol) (4.6g is 32mmol) in two with 1-sec.-propyl-4-piperidone to the 4-hydrazino-benzoic acid
Figure BSA00000321451201424
Add dense HCl (10mL) in the solution in the alkane (100mL), and with this mixture 100 ℃ of heated overnight.Remove then and desolvate, this yellow solid (12g) need not to be further purified and promptly can be used for next step, crude product and two
Figure BSA00000321451201431
Alkane compound (～2: 1).MS(M+1)：259.00。
Step B:2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201432
According to the method that is similar to embodiment 1 step C, by thick 2-sec.-propyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid and 4-methyl piperidine, preparation title compound.MS(M+1)：340.0。
Embodiment 141.5-benzyl-2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201433
Under room temperature and nitrogen atmosphere, with 60%NaH (32mg 0.80mmol) whole part adds to 2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (75mg is 0.22mmol) in the suspension in DMF (2mL) for indoles.This mixture was stirred 30 minutes, add (brooethyl) benzene (31 μ L, 0.26mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo also is dissolved in methylene dichloride with resistates, washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product, and it is by reversed-phase HPLC (5-75%CH 3CN) purifying obtains title compound, and it is white solid (24mg).MS(M+1)：430.0。 1H?NMR(400MHz，CDCl 3)δppm?0.97(d，J＝6.25Hz，3H)，1.05-1.35(m，1H)，1.47(dd，J＝19.53，6.64Hz，5H)，1.56-1.87(m，1H)，2.51-3.13(m，5H)，2.87(d，J＝17.77Hz，1H)，3.18-3.53(m，2H)，3.78-3.94(m，3H)，4.20(d，J＝13.28Hz，1H)，4.55-4.80(m，1H)，4.60(d，J＝13.86Hz，2H)，5.26(d，J＝7.42Hz，2H)，6.93(d，J＝6.05Hz，2H)，7.07-7.36(m，5H)，7.52(s，1H)。
Embodiment 142.2-sec.-propyl-5-(4-methoxy-benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201441
Under room temperature and nitrogen atmosphere, with 60%NaH (28mg 0.70mmol) whole part adds to 2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (73mg is 0.21mmol) in the suspension in DMF (1.5mL) for indoles.This mixture was stirred 30 minutes, add 1-(chloromethyl)-4-anisole (58 μ L, 0.43mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo, resistates are dissolved in methylene dichloride and wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product, and it is by reversed-phase HPLC (5-75%CH 3CN) purifying obtains the tfa salt (8mg) of title compound.MS(M+1)：460.0。 1H?NMR(400MHz，CDCl 3)δppm?0.98(d，J＝6.44Hz，3H)，1.05-1.33(m，3H)，1.47(dd，J＝17.87，6.54Hz，6H)，1.55-1.86(m，3H)，2.75-3.10(m，1H)，2.86(d，J＝15.43Hz，1H)，3.17-3.48(m，2H)，3.74(s，3H)，3.72-3.92(m，2H)，4.20(d，J＝16.01Hz，1H)，4.60(d，J＝13.28Hz，1H)，4.53-4.82(m，2H)，5.12-5.25(m，2H)，6.75-6.91(m，4H)，7.14-7.28(m，2H)，7.52(s，1H)。
Embodiment 143.2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-amyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Under room temperature and nitrogen atmosphere, with 60%NaH (32mg 0.80mmol) whole part adds to 2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (75mg is 0.22mmol) in the suspension in DMF (2mL) for indoles.This mixture was stirred 30 minutes, add the 1-bromo pentane silane (55 μ L, 0.44mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo is dissolved in methylene dichloride with resistates and washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product, and it is by reversed-phase HPLC (5-75%CH 3CN) purifying obtains the tfa salt (13mg) of title compound.MS(M+1)：410.2。 1H?NMR(400MHz，CD 3OD)δppm? 1H?NMR(400MHz，CD 3OD)δppm?0.79(t，J＝7.03Hz，3H)，0.89(d，J＝6.44Hz，3H)，0.94-1.32(m，4H)，1.40(d，J＝6.45Hz，6H)，1.45-1.74(m，3H)，3.16(t，J＝5.66Hz，2H)，3.37-3.55(m，2H)，3.63-3.86(m，2H)，4.04-4.14(m，2H)，4.36-4.58(m，2H)，7.16(d，J＝8.59Hz，1H)，7.40(d，J＝8.59Hz，1H)，7.49(s，1H)。
Embodiment 144.2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201451
Under room temperature and nitrogen atmosphere, with 60%NaH (33mg 0.82mmol) whole part adds to 2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (75mg is 0.22mmol) in the suspension in DMF (1.5mL) for indoles.This mixture was stirred 30 minutes, add the 1-N-PROPYLE BROMIDE (40 μ L, 0.44mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo also is dissolved in methylene dichloride with resistates, washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product, and it obtains the tfa salt (8mg) of title compound by the reversed-phase HPLC purifying.MS(M+1)：382.0。 1H?NMR(400MHz，CDCl 3)δppm?0.88(t，J＝7.42Hz，3H)，0.98(d，J＝6.44Hz，3H)，1.07-1.33(m，2H)，1.47(dd，J＝17.48，6.54Hz，6H)，1.57-1.84(m，6H)，2.74-3.08(m，2H)，2.96(d，J＝16.79Hz，1H)，3.22-3.40(m，1H)，3.41-3.58(m，1H)，3.75-4.10(m，5H)，4.18(d，J＝13.67Hz，1H)，4.54(d，J＝13.86Hz，1H)，7.17-7.33(m，2H)，7.47(s，1H)。
Embodiment 145.5-[(6-chloro-1,3-benzodioxole-5-yl) methyl]-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201452
Steps A: carbonyl 2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl)]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201461
2-sec.-propyl-2,3 in being dissolved in DMF (5mL), 4, in the solution of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid (1.65mmol), add 4-methoxyl group piperidines (1.65mmol) successively, diisopropyl ethyl amine (1.65mmol) and HATU (522mg, 1.65mmol).With this mixture in stirred overnight at room temperature.Solvent removed in vacuo, resistates water (10mL) are handled and with methylene dichloride (2x20mL) extraction, are used Na 2SO 4Dry also evaporation.Resistates obtains required product (230mg, 39%) by purification by flash chromatography.MS(M+1)：356.3。
Step B:5-[(6-chloro-1,3-benzodioxole-5-yl) methyl]-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201462
To 2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4, (75mg 0.21mmol) in the solution in dry DMF (3mL), adds 60%NaH (0.42mmol) to 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.This mixture was stirred 30 minutes at 0 ℃, add 5-chloro-6-(chloromethyl)-1 then, and the 3-benzodioxole (62mg, 0.3mmol).Treat that after stirred overnight at room temperature solvent removed in vacuo also is dissolved in methylene dichloride (20mL) with resistates, dried over sodium sulfate is used in water (10mL) washing.Removing desolvates obtains crude product, and it obtains the tfa salt (32mg, 24%) of required product by the reversed-phase HPLC purifying.MS(M+1)：524.0。 1H?NMR(400MHz，CD 3OD)δppm?1.44-1.54(m，9H)，1.83(m，3H)，3.16(m，3H)，3.37(s，3H)，3.53(m，3H)，3.78(m，1H)，3.87(m，1H)，4.53(m，1H)，4.66(m，1H)，5.42(m，2H)，5.90(s，1H)，5.91(s，2H)，6.97(s，1H)，7.27(d，J＝8.54Hz，1H)，7.41(d，J＝8.54Hz，1H)，7.67(s，1H)。
Embodiment 146.5-(4-ethoxy benzyl)-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201471
To 2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4, (75mg 0.21mmol) in the solution in dry DMF (3mL), adds 60%NaH (0.42mmol) to 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.This mixture was stirred 30 minutes at 0 ℃, add 1-(chloromethyl)-4-phenetole (0.3mmol) then.Treat that after stirred overnight at room temperature solvent removed in vacuo also is dissolved in methylene dichloride (20mL) with resistates, dried over sodium sulfate is used in water (10mL) washing.Removing desolvates obtains crude product, and it obtains the tfa salt (46mg, 36%) of required product by the reversed-phase HPLC purifying.MS(M+1)：490.0。 1H?NMR(400MHz，CD 3OD)δppm?1.33(t，J＝7.03Hz，3H)，1.40(t，J＝6.83Hz，4H)，1.48(dd，J＝6.06，1.17Hz，6H)，2.85(s，3H)，3.19(m，1H)，3.36(s，3H)，3.53(m，2H)，3.81(m，2H)，3.96(q，J＝7.03Hz，2H)，4.07(m，2H)，4.46(s，2H)，4.59(m，1H)，5.35(m，1H)，6.81(d，J＝8.59Hz，1H)，7.03(m，3H)，7.45(d，J＝8.59Hz，2H)，7.64(s，1H)。
Embodiment 147.5-(2, the 6-difluorobenzyl)-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201472
To 2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4, (75mg 0.21mmol) in the solution in dry DMF (3mL), adds 60%NaH (0.42mmol) to 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.This mixture was stirred 30 minutes at 0 ℃, add 2-(brooethyl)-1 then, 3-two fluorobenzene (0.3mmol).Treat that after stirred overnight at room temperature solvent removed in vacuo also is dissolved in methylene dichloride (20mL) with resistates, dried over sodium sulfate is used in water (10mL) washing.Removing desolvates obtains crude product, and it obtains the tfa salt (53mg, 42%) of required product by the reversed-phase HPLC purifying.MS(M+1)：482.0。 1H?NMR(400MHz，CD 3OD)δppm?1.49(dd，J＝6.45，2.74Hz，6H)，1.52-2.06(m，4H)，3.18-3.38(m，3H)，3.36(s，3H)，3.47-3.72(m，4H)，3.77(m，1H)，3.90(m，1H)，4.00(m，1H)，4.53(m，2H)，5.48(m，2H)，7.03(m，2H)，7.25(dd，J＝8.50，1.37Hz，1H)，7.40(m，1H)，7.56(d，J＝8.50Hz，1H)，7.59(s，1H)。
Embodiment 148.5-(4-ethoxy benzyl)-8-[(4-oxyethyl group piperidines-1-yl) carbonyl]-2-sec.-propyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201481
Steps A: carbonyl 8-[(4-oxyethyl group piperidines-1-yl)]-2-sec.-propyl-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201482
To 2-sec.-propyl-2,3,4, in 5-tetrahydrochysene-1H-pyrido [4, the 3-b] indoles-solution of 8-carboxylic acid (1.2mmol) in DMF (3mL), add successively 4-oxyethyl group piperidines (1.2mmol, according to literature method preparation, referring to Grob, C.A.; Krasnobajew, V.Helvetica Chimica Acta 1964,47,2145), diisopropyl ethyl amine (1.2mmol) and HATU (1.44mmol).With this mixture in stirred overnight at room temperature.Solvent removed in vacuo, resistates water (10mL) are handled and with methylene dichloride (2 x 20mL) extraction, are used Na 2SO 4Dry also evaporation.Resistates obtains required product (70mg, 16%) by purification by flash chromatography.MS(M+1)：370.4。
Step B:5-(4-ethoxy benzyl)-8-[(4-oxyethyl group piperidines-1-yl) carbonyl]-2-sec.-propyl-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
To 8-[(4-oxyethyl group piperidines-1-yl) carbonyl]-2-sec.-propyl-2,3,4, (70mg 0.19mmol) in the solution in dry DMF (3mL), adds 60%NaH (0.38mmol) to 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.This mixture was stirred 30 minutes at 0 ℃, add 1-(chloromethyl)-4-phenetole (0.28mmol) then.Treat that after stirred overnight at room temperature solvent removed in vacuo also is dissolved in methylene dichloride (20mL) with resistates, dried over sodium sulfate is used in water (10mL) washing.Removing desolvates obtains crude product, and it obtains the tfa salt (63mg, 54%) of required product by the reversed-phase HPLC purifying.MS(M+1)：504.0。 1H?NMR(400MHz，CD 3OD)δppm?1.19(t，J＝7.03Hz，3H)，1.33(t，J＝6.83Hz，3H)，1.48(dd，J＝6.05，0.97Hz，6H)，1.75-2.05(m，4H)，3.15-3.25(m，2H)，3.50-3.68(m，6H)，3.80(m，2H)，3.97(q，J＝7.03Hz，2H)，4.49(m，1H)，4.63(m，1H)，5.28-5.46(m，4H)，6.81(d，J＝8.72Hz，2H)，7.03(d，J＝8.72Hz，2H)，7.26(dd，J＝8.45，1.27Hz，1H)，7.54(d，J＝8.45Hz，1H)，7.64(s，1H)。
Embodiment 149.2-cyclopentyl-8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201491
Steps A: 8-[(4,4-difluoro piperidines-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201492
With 2-(tert-butoxycarbonyl)-2,3,4, (284mg 0.9mmol) is dissolved in DMF (3mL) to 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid, and add 3-methyl piperidine (1.35mmol) successively, and diisopropyl ethyl amine (1.08mmol) and HATU (410mg, 1.08mmol).With this mixture stirring at room 5 hours.Solvent removed in vacuo, resistates water (10mL) are handled and with methylene dichloride (2x20mL) extraction, are used Na 2SO 4Dry also evaporation obtains crude product (361mg, 96%), and it is used for next step without purifying.MS(M+1)：420.1。
Step B:8-[(4,4-difluoro piperidines-1-yl) carbonyl]-the 5-methyl isophthalic acid, 3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201501
At 0 ℃, with crude product 8-[(4,4-difluoro piperidines-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] (361mg 0.86mmol) handled 30 minutes in DMF (10mL) with 60%NaH (1.72mmol) the Indoline-2-carboxylic acid tert-butyl ester, added methyl iodide (1.03mmol) then.Treat that after stirring at room 2 hours solvent removed in vacuo also is dissolved in methylene dichloride (50mL) with resistates, dried over sodium sulfate is used in water (20mL) washing.Removing desolvates obtains crude product (372mg, 99%), and it need not to be further purified and can use.MS(M+1)：434.4。
Step C:8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
To 8-[(4,4-difluoro piperidines-1-yl) carbonyl]-the 5-methyl isophthalic acid, 3,4, (372mg is 0.86mmol) in two for 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester In the solution in the alkane (5mL), add 4NHCl/ two
Figure BSA00000321451201504
Alkane (4mL).With this solution stirring at room 5 hours.Solvent removed in vacuo, resistates washs with diethyl ether, filters, and obtains the HCl salt (305mg, 96%) of required product, and it need not to be further purified and can use.MS(M+1)：334.0。
Step D:2-cyclopentyl-8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201505
With thick 8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (HCl salt, 0.2mmol, 74mg) in methylene dichloride (4mL), handle with cyclopentanone (0.4mmol) and sodium triacetoxy borohydride (0.3mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (28mg, 27%) of required product.MS(M+1)：402.0。 1H?NMR(600MHz，CDCl 3)δppm1.69(m，2H)，1.92(m，2H)，1.98-2.22(m，8H)，3.04(m，1H)，3.44(m，2H)，3.50(s，2H)，3.65(m，2H)，3.70(s，3H)，4.00(m，2H)，4.20(d，J＝14.08Hz，1H)，4.81(d，J＝14.08Hz，1H)，7.28(d，J＝8.45Hz，1H)，7.34(d，J＝8.45Hz，1H)，7.55(s，1H)。
Embodiment 150.8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201511
With thick 8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (HCl salt, 0.2mmol 74mg) handle in methylene dichloride (4mL) with tetrahydrochysene-4H-pyrans-4-ketone (0.4mmol) and sodium triacetoxy borohydride (0.3mmol) indoles.This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (52mg, 49%) of required product.MS(M+1)：418.0。 1H?NMR(600MHz，CDCl 3)δppm?1.89-2.22(m，8H)，3.04(m，1H)，3.31-3.54(m，4H)，3.68(s，3H)，3.75(m，3H)，3.95(m，1H)，4.17(d，J＝10.75Hz，2H)，4.29(d，J＝13.31Hz，1H)，4.67(d，J＝13.31Hz，1H)，5.30(m，2H)，7.28(d，J＝8.19Hz，1H)，7.33(d，J＝8.19Hz，1H)，7.54(s，1H)。
Embodiment 151.8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201512
According to the identical method of embodiment 1 step e, with thick 8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (HCl salt, 0.15mmol, 55mg) in methylene dichloride (3mL), handle with dihydrofuran-3 (2H)-ketone (0.3mmol) and sodium triacetoxy borohydride (0.23mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (23mg, 30%) of required product.MS(M+1)：404.0。 1H?NMR(600MHz，CDCl 3)δppm?1.89-2.16(m，4H)，2.45(m，2H)，3.41(m，2H)，3.50(s，2H)，3.69(s，3H)，3.73-4.05(m，7H)，4.19(m，1H)，4.25(m，1H)，4.35(dd，J＝11.01，2.30Hz，1H)，4.66(m，1H)，7.29(d，J＝8.45Hz，1H)，7.33(d，J＝8.45Hz，1H)，7.53(s，1H)。
Embodiment 152.5-allyl group-2-(cyclobutyl)-8-[(3-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201521
Steps A: carbonyl 8-[(3-methyl piperidine-1-yl)]-1,3,4,4a, 5, the preparation of 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201522
With 2-(tert-butoxycarbonyl)-2,3,4, (316mg 1.0mmol) is dissolved in DMF (3mL) to 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid, and add 3-methyl piperidine (1.5mmol) successively, and diisopropyl ethyl amine (1.2mmol) and HATU (456mg, 1.2mmol).With this mixture stirring at room 3 hours.Solvent removed in vacuo, resistates water (10mL) are handled and with methylene dichloride (2x20mL) extraction, are used Na 2SO 4Drying is also evaporated, and obtains the yellow solid of crude product.This group product is used for next step without purifying.MS(M+1)：398.1。
Step B:5-allyl group-8-[(3-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
At 0 ℃, with crude product 8-[(3-methyl piperidine-1-yl) carbonyl]-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (1.0mmol) were handled 30 minutes in DMF with 60%NaH (2mmol), added allyl bromide 98 (1.5mmol) then.Treat that after stirring at room 2 hours solvent removed in vacuo also is dissolved in methylene dichloride (20mL) with resistates, dried over sodium sulfate is used in water (10mL) washing.Removing desolvates obtains crude product, and it obtains required product (328mg, two steps 75%) by the short pad of silica gel (0-30%EtOAc/ methylene dichloride) purifying.MS(M+1)：438.1。
Step C:5-allyl group-8-[(3-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201532
To 5-allyl group-8-[(3-methyl piperidine-1-yl) carbonyl]-1,3,4, add trifluoroacetic acid (20eq.) in the solution of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (328mg) in methylene dichloride (5mL), and in stirring at room 1 hour.Vacuum is removed excessive trifluoroacetic acid, obtains thick 5-allyl group-8-[(3-methyl piperidine-1-yl) carbonyl]-2,3,4, the trifluoroacetic acid salt form of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.
Step D:5-allyl group-2-(cyclobutyl)-8-[(3-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201533
With thick 5-allyl group-8-[(3-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (tfa salt, 0.175mmol 60mg) handle in methylene dichloride with cyclobutanone (0.35mmol) and sodium triacetoxy borohydride (0.26mmol) indoles.This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains required product 5-allyl group-2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] tfa salt (28mg, 32%) of indoles.MS(M+1)：392.0。 1H?NMR(400MHz，CDCl 3)δppm?0.70-1.07(m，3H)，1.10-1.40(m，3H)，1.48-2.03(m，6H)，2.23-2.42(m，2H)，2.50-2.76(m，2H)，2.85-3.01(m，2H)，3.20-3.29(m，2H)，3.60-4.00(m，5H)，4.50-4.75(m，2H)，4.79(d，J＝17.18Hz，1H)，5.17(d，J＝10.35Hz，1H)，5.85-6.00(m，1H)，7.20-7.32(m，2H)，7.49(s，1H)。
Embodiment 153.5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylate methyl ester
Figure BSA00000321451201541
Steps A: 5-methyl isophthalic acid, 3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2, the preparation of 8-dicarboxylic acid 2-tertiary butyl ester 8-methyl ester
Under 0 ℃ and nitrogen atmosphere, to 2-(tert-butoxycarbonyl)-2,3,4,4a, 5, (3.16g 10mmol) adds 60%NaH (80mmol) in the solution in dry DMF (50mL) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-carboxylic acid.This mixture stirring at room 30 minutes, is added methyl iodide (80mmol) in room temperature then, and with reaction mixture in stirred overnight at room temperature.Solvent removed in vacuo also is dissolved in methylene dichloride (200mL) with resistates, and dried over sodium sulfate is used in water (50mL) washing.Removing desolvates obtains crude product (3.14g, 91%), and it need not to be further purified and can use.MS(M+1)：345.3。
Step B:5-methyl-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylate methyl ester
Figure BSA00000321451201543
According to the identical method of embodiment 1 step D (method B), with 5-methyl isophthalic acid, 3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2,8-dicarboxylic acid 2-tertiary butyl ester 8-methyl ester (3.14g, 9.13mmol) with trifluoroacetic acid in methylene dichloride in room temperature treatment 1 hour.Vacuum is removed excessive trifluoroacetic acid, obtains the trifluoroacetic acid salt form (3.44g, 96%) of crude product.MS(M+1)：244.9。
Step C:5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylate methyl ester
Figure BSA00000321451201551
To 5-methyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylate methyl ester (tfa salt, 2.83g, 7.9mmol) in methylene chloride (1: 1v/v, in the solution 80mL), add triethylamine (7.9mmol), then add tetrahydrochysene-4H-pyrans-4-ketone (11.9mmol) and sodium cyanoborohydride (11.9mmol).This mixture is spent the night 50 ℃ of stirrings, then add another part tetrahydrochysene-4H-pyrans-4-ketone (7.9mmol) and sodium cyanoborohydride (7.9mmol).Treat after 50 ℃ are stirred other 24 hours, solvent removed in vacuo, and resistates is absorbed in the methylene dichloride (100mL), use saturated NaHCO 3Na is used in solution (50mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates carries out purifying through the short pad of silica gel, obtains required product, and it is white solid (2.41g, 93%).MS(M+1)：329.0。 1H?NMR(600MHz，CD 3OD)δppm?1.88-2.00(m，2H)，2.13-2.25(m，2H)，3.24-3.35(m，2H)，3.46-3.65(m，3H)，3.71-3.75(m，1H)，3.77(s，3H)，3.92(s，3H)，4.00-4.09(m，1H)，4.10-4.19(m，2H)，4.55(d，J＝12.03Hz，1H)，4.70-4.82(m，1H)，7.50(d，J＝8.70Hz，1H)，7.92(d，J＝8.70Hz，1H)，8.30(s，1H)。
Embodiment 154.1-{[5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidines-4-methane amide
Figure BSA00000321451201552
Steps A: 5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid
Figure BSA00000321451201561
To 5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, (580mg is 1.77mmol) in tetrahydrofuran (THF)/methanol (1: 1: 1v/v for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylate methyl ester, in the solution 15mL), and adding KOH (297mg, 5.31mmol).Reaction mixture was stirred 3 hours at 80 ℃.To be cooled to room temperature, this solution is neutralized to pH～5.0 with 1M HCl, concentrate, solid is at methylene chloride (v/v 1: 1, refluxed 5 minutes 80mL), by diatomite filtration, concentrated filtrate, obtain required product, it is white solid (420mg, 76%).MS(M+1)：315.0。
Step B:1-{[5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } preparation of piperidines-4-methane amide
Figure BSA00000321451201562
(2-(tert-butoxycarbonyl)-2 in being dissolved in DMF (3mL), 3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (57mg in solution 0.18mmol), adds six hydrogen Isonicotinamides (0.22mmol) to indoles-8-carboxylic acid successively, diisopropyl ethyl amine (0.22mmol) and HATU (84mg, 0.22mmol).With this mixture stirring at room 3 hours.Solvent removed in vacuo, resistates water (10mL) are handled and with methylene dichloride (2x20mL) extraction, are used Na 2SO 4Dry also evaporation.Resistates reversed-phase HPLC purifying obtains the tfa salt (31mg, 32%) of required product.MS(M+1)：425.0。 1H?NMR(600MHz，CD 3OD)δppm?1.66-1.79(m，2H)，1.89-1.99(m，2H)，2.00-2.07(m，2H)，2.15-2.25(m，2H)，2.53-2.61(m，1H)，3.27-3.32(m，4H)，3.47-3.56(m，3H)，3.57-3.64(m，1H)，3.69-3.76(m，2H)，3.78(s，3H)，4.02-4.09(m，1H)，4.11-4.19(m，2H)，4.50-4.58(m，1H)，4.72-4.79(m，1H)，7.31(d，J＝8.45Hz，1H)，7.52(d，J＝8.45Hz，1H)，7.64(s，1H)。
Embodiment 155-175: the following examples (table 4) by with embodiment 154 step B in the preparation of identical method.
Table 4
Figure BSA00000321451201571
Figure BSA00000321451201581
Figure BSA00000321451201591
Figure BSA00000321451201601
Figure BSA00000321451201611
Embodiment 176.N-(5-allyl group-2-cyclopentyl-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N-methyl benzenesulfonamide
Figure BSA00000321451201612
Steps A: 5-allyl group-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] indoles-2, the preparation of 8-dicarboxylic acid 8-allyl ester 2-tertiary butyl ester
Under 0 ℃ and nitrogen atmosphere, to 2-(tert-butoxycarbonyl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-carboxylic acid (2.6g, 8.2mmol) in the solution in dry DMF (30mL), whole part of ground add 60%NaH (984mg, 24.6mmol).With this mixture stirring at room 30 minutes, then room temperature add allyl bromide 98 (2.1mL, 24.6mmol), and with reaction mixture in stirred overnight at room temperature.Solvent removed in vacuo also is dissolved in methylene dichloride (200mL) with resistates, and dried over sodium sulfate is used in water (50mL) washing.Removing desolvates obtains crude product, and it carries out purifying by silica gel (5-60%EtOAc/ methylene dichloride), obtains required product, and it is yellow oil (1.58g, 48%).MS(M+1)：397.3。
Step B:5-allyl group-2-(tert-butoxycarbonyl)-2,3,4,4a, 5, the preparation of 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-carboxylic acid
Figure BSA00000321451201621
To 5-allyl group-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] indoles-2, (900mg is 2.27mmol) in two for 8-dicarboxylic acid 8-allyl ester 2-tertiary butyl ester Alkane/methanol (1: 1: 1v/v, 15mL) in the solution in, adding LiOH (136mg, 5.68mmol).Reaction mixture was stirred 3 hours at 80 ℃.To be cooled to room temperature, reaction mixture is concentrated, add water (10mL) then.This solution is neutralized to pH～5.0 with HOAc, by filtering the collecting precipitation thing, obtains required product, it is white solid (560mg, 69%).MS(M+1)：357.0。
Step C:5-allyl group-8-({ [2-(trimethyl silyl) oxyethyl group] carbonyl } amino)-1,3,4,4a, 5, the preparation of 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
To 5-allyl group-2-(tert-butoxycarbonyl)-2; 3; 4; 4a, 5,9b-six hydrogen-1H-pyrido [4; 3-b] indoles-8-carboxylic acid (190mg; 0.53mmol) add diphenyl phosphoryl azide (0.64mmol) in the suspension in dry toluene (12mL), then add triethylamine (0.64mmol), add trimethyl silyl ethanol (1.06mmol) then.This mixture was stirred 6 hours at 100 ℃.To be cooled to room temperature, reaction mixture is concentrated, add methylene dichloride (20mL) then, with saturated sodium bicarbonate (10mL) washing, use dried over sodium sulfate.Removing desolvates obtains crude product, and this crude product obtains required product through silica gel (5%EtOAc/ methylene dichloride) purifying, and it is yellow oil (225mg, 90%).MS(M+1)：472.3。 1H?NMR(400MHz，CDCl 3)δppm?0.04(s，9H)，1.00-1.07(m，2H)，1.48(s，9H)，2.72(s，2H)，3.79(s，2H)，4.22-4.27(m，2H)，4.54-4.62(m，4H)，4.82(d，J＝17.18Hz，1H)，5.08(d，J＝10.15Hz，1H)，5.80-5.92(m，1H)，6.70(s，1H)，6.98(s，1H)，7.13(d，J＝8.59Hz，1H)，7.66(s，1H)。
Step D:5-allyl group-8-(methyl { [2-(trimethyl silyl) oxyethyl group] carbonyl } amino)-1,3,4,4a, 5, the preparation of 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201631
Under 0 ℃ and nitrogen atmosphere, to 5-allyl group-8-({ [2-(trimethyl silyl) oxyethyl group] carbonyl } amino)-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] (225mg, 0.48mmol) in the solution in dry DMF (5mL), whole part of ground adds 60%NaH (0.72mmol) to the Indoline-2-carboxylic acid tert-butyl ester.This mixture stirring at room 30 minutes, is added methyl iodide (0.72mmol) in room temperature then, and with reaction mixture stirring at room 3 hours.Solvent removed in vacuo also is dissolved in methylene dichloride (20mL) with resistates, and dried over sodium sulfate is used in water (10mL) washing.Removing desolvates obtains crude product, and it need not to be further purified and can use.MS(M+1)：486.1。
Step e: 5-allyl group-8-(methylamino)-1,3,4,4a, 5, the preparation of 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201632
To thick 5-allyl group-8-(methyl { [2-(trimethyl silyl) oxyethyl group] carbonyl } amino)-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] (1M is in THF, 0.5mL) to add TBAF in the solution of the Indoline-2-carboxylic acid tert-butyl ester (0.48mmol) in anhydrous THF (6mL).With this solution stirring at room 3 hours.Solvent removed in vacuo also is dissolved in methylene dichloride (20mL) with resistates, with saturated sodium bicarbonate (10mL) washing, uses dried over sodium sulfate.Removing desolvates obtains crude product, and it need not to be further purified and can use.MS(M+1)：342.1。
Step F: 5-allyl group-8-[methyl (benzenesulfonyl) amino]-1,3,4,4a, 5, the preparation of 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201633
To thick 5-allyl group-8-(methylamino)-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester (embodiment XL-4G, 0.48mmol) add benzene sulfonyl chloride (0.96mmol) in the solution in anhydrous methylene chloride (5mL), add triethylamine (0.96mmol) then.With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (20mL), and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains required product by flash chromatography (20% ethyl acetate is in hexane) purifying, and it is oily matter (103mg, three steps 45%).MS(M+1)：482.3。
The preparation of step G:N-(5-allyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N-methyl benzenesulfonamide
Figure BSA00000321451201641
To 5-allyl group-8-[methyl (benzenesulfonyl) amino]-1,3,4,4a, 5, (103mg is 0.21mmol) in two for 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester In the solution in the alkane (2mL), add the HCl/ two of 4N
Figure BSA00000321451201643
Alkane (1.5mL).With this solution stirring at room 3 hours.Solvent removed in vacuo also is dissolved in methylene dichloride (30mL) with resistates, with saturated sodium bicarbonate (10mL) washing, uses dried over sodium sulfate.Removing desolvates obtains required product, and it need not to be further purified and can use.MS(M+1)：382.3。
The preparation of step H:N-(5-allyl group-2-cyclopentyl-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N-methyl benzenesulfonamide
Figure BSA00000321451201644
With N-(5-allyl group-2-cyclopentyl-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-(0.1mmol 48mg) handles in methylene dichloride with cyclopentanone (0.2mmol) and sodium triacetoxy borohydride (0.15mmol) the N-methyl benzenesulfonamide.This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (16mg, 28%) of required product.MS(M+1)：450.0。 1H?NMR(400MHz，CDCl 3)δppm?1.24(s，1H)，1.58-1.73(m，2H)，1.82-1.96(m，2H)，1.97-2.21(m，4H)，2.89-3.01(m，1H)，3.21(s，3H)，3.30-3.44(m，2H)，3.59(m，1H)，3.91(m，1H)，4.12(d，J＝14.06Hz，1H)，4.62(s，2H)，4.68(d，J＝14.25Hz，1H)，4.80(d，J＝16.99Hz，1H)，5.14(d，J＝10.15Hz，1H)，5.79-5.96(m，1H)，6.84(d，J＝9.96Hz，1H)，7.09-7.19(m，2H)，7.43(t，J＝7.71Hz，2H)，7.57(t，J＝8.20Hz，3H)。
Embodiment 177.N-methyl-N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] benzsulfamide
Figure BSA00000321451201651
Steps A: N-[5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl]-preparation of N-methyl benzenesulfonamide
With N-(5-allyl group-2-cyclopentyl-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-(0.05mmol 20mg) handles in methylene dichloride (2mL) with tetrahydrochysene-4H-pyrans-4-ketone (0.1mmol) and sodium triacetoxy borohydride (0.075mmol) the N-methyl benzenesulfonamide.This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates need not to be further purified and can use.MS(M+1)：466.1。
Step B:N-methyl-N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] preparation of benzsulfamide
Figure BSA00000321451201661
Under 5%Pd/C existence and 30psi (room temperature), with thick N-[5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl]-the solution hydrogenation of N-methyl benzenesulfonamide (0.05mmol) in methyl alcohol (5mL) 3 hours.After the filtration, with solution concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (6mg, two step 21%) of required product.MS(M+1)：468.1。 1H?NMR(600MHz，CDCl 3)δppm?0.99(m，3H)，1.34(m，2H)，2.14(m，3H)，2.25(m，1H)，3.06(m，1H)，3.32(s，3H)，3.45(m，1H)，3.57(m，2H)，3.64(m，1H)，3.80(m，1H)，4.06(m，3H)，4.27(m，3H)，4.63(m，1H)，6.92(m，1H)，7.27(m，2H)，7.56(m，2H)，7.68(m，3H)。
Embodiment 178.N-[5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] benzsulfamide
Figure BSA00000321451201662
Steps A: the preparation of (5-allyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) carboxylamine 2-(trimethyl silyl) ethyl ester
To thick 5-allyl group-8-({ [2-(trimethyl silyl) oxyethyl group] carbonyl } amino)-1,3,4,4a, 5, (930mg is 1.97mmol) in two for 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201664
In the solution in the alkane (10mL), add 4N HCl/ two
Figure BSA00000321451201665
Alkane (6mL).With this solution stirring at room 3 hours.Solvent removed in vacuo, resistates washs with diethyl ether, and solid by filtration is collected and vacuum-drying, obtains the HCl salt (620mg, 76%) of required product, and it need not to be further purified and can use.MS(M+1)：372.1。
Step B:[5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] preparation of carboxylamine 2-(trimethyl silyl) ethyl ester
Figure BSA00000321451201671
With (5-allyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) carboxylamine 2-(trimethyl silyl) ethyl ester (HCl salt, 310mg 0.76mmol) handles with triethylamine (0.76mmol), then handles in methylene dichloride (20mL) with tetrahydrochysene-4H-pyrans-4-ketone (1.52mmol) and sodium triacetoxy borohydride (1.14mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (50mL) dilution, is used saturated NaHCO 3Na is used in solution (20mL) washing 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates obtains required product (90mg, 27%) through the short pad of silica gel (30～90% ethyl acetate are in methylene dichloride) purifying.MS(M+1)：456.4。
Step C:5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5, the preparation of 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine
To [5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] (90mg, (1M is in THF, 0.5mL) 0.2mmol) to add TBAF in the solution in anhydrous THF (3mL) for carboxylamine 2-(trimethyl silyl) ethyl ester.With this solution stirring at room 3 hours.Solvent removed in vacuo also is dissolved in methylene dichloride (20mL) with resistates, with saturated sodium bicarbonate (10mL) washing, uses dried over sodium sulfate.Removing desolvates obtains crude product (62mg, 99%), and it need not to be further purified and can use.MS(M+1)：312.1。
Step D:N-[5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] preparation of benzsulfamide
Figure BSA00000321451201681
To thick 5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] (32mg 0.1mmol) adds benzene sulfonyl chloride (0.11mmol) in the solution in anhydrous methylene chloride (2mL) to indoles-8-amine, adds triethylamine (0.2mmol) then.With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (10mL), and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product carries out purifying by reversed-phase HPLC, obtains the tfa salt (34mg, 60%) of required product.MS(M+1)：452.0。 1H?NMR(600MHz，CDCl 3)δppm1.42(m，2H)，1.60-1.73(m，2H)，3.03(m，2H)，3.21(m，2H)，3.32(m，1H)，3.50(m，2H)，3.80(m，1H)，3.91(m，1H)，4.16(d，J＝9.73Hz，2H)，4.24(m，1H)，4.62(m，1H)，4.74(d，J＝17.15Hz，1H)，5.11(d，J＝10.50Hz，1H)，5.84(m，1H)，6.76(d，J＝8.19Hz，1H)，7.02(d，J＝8.70Hz，1H)，7.23(s，1H)，7.39(m，3H)，7.50(m，1H)，7.70(d，J＝7.68Hz，2H)。
Embodiment 179.5-allyl group-2-cyclopentyl-8-nitro-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201682
Steps A: 8-nitro-2,3,4,4a, 5, the preparation of 9b-six hydrogen-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201683
In sealed tube, in the mixture of 4-nitrophenyl hydrazonium salt hydrochlorate (5mmol) and 4-piperidone monohydrate hydrochloride (5mmol), add formic acid (5mL) and spend the night 120 ℃ of stirrings.To be cooled to room temperature, add two Alkane (5mL) solid collected by filtration obtains required product, and it is the brown solid (560mg, 43%) of formate form.MS(M+1)：217.9。
Step B:2-cyclopentyl-8-nitro-2,3,4,4a, 5, the preparation of 9b-six hydrogen-1H-pyrido [4,3-b] indoles
To 8-nitro-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles (HCOOH salt, 1.5g,, 5.73mmol) add triethylamine (8.60mmol) in the suspension in methyl alcohol (80mL), then add cyclopentanone (8.60mmol) and sodium cyanoborohydride (11.5mmol).This mixture is spent the night 50 ℃ of stirrings.Add another normal sodium cyanoborohydride (5.73mmol), and stirred 6 hours at 50 ℃.Under reduced pressure remove and desolvate, resistates is absorbed in the methylene dichloride (100mL), with saturated sodium bicarbonate (20mL) washing, uses dried over sodium sulfate.Removing desolvates obtains crude product (903mg, 55%), and it need not to be further purified and can use.MS(M+1)：286.0。Sedimentary during this time surplus stock by filtered and recycled (～810mg).
Step C:5-allyl group-2-cyclopentyl-8-nitro-2,3,4,4a, 5, the preparation of 9b-six hydrogen-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201693
At 0 ℃, with 2-cyclopentyl-8-nitro-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles (4.2mmol) were handled 30 minutes in DMF (25mL) with 60%NaH (8.4mmol), added allyl bromide 98 (5.04mmol) then.Treat that after stirred overnight at room temperature solvent removed in vacuo also is dissolved in methylene dichloride (80mL) with resistates, dried over sodium sulfate is used in water (20mL) washing.Removing desolvates obtains crude product, and this crude product obtains required product by flash chromatography (10-80%EtOAc/ methylene dichloride) purifying, and it is brown oily matter (1.3g, 95%).MS(M+1)：326.29。The sample that is used for biological test is further purified by reversed-phase HPLC, obtains tfa salt, and it is a pale yellow powder. 1H?NMR(600MHz，CDCl 3)δppm?1.70(m，4H)，1.95(m，2H)，2.17(m，2H)，2.97(m，1H)，3.34(m，1H)，3.60(m，2H)，4.03(m，1H)，4.19(m，1H)，4.73(m，2H)，4.81(m，1H)，4.87(d，J＝14.34Hz，1H)，5.22(d，J＝10.50Hz，1H)，5.94(m，1H)，7.33(d，J＝8.96Hz，1H)，8.16(d，J＝8.96Hz，1H)，8.42(s，1H)。
Embodiment 180.5-allyl group-8-nitro-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201701
Steps A: 8-nitro-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5, the preparation of 9b-six hydrogen-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201702
To 8-nitro-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles (HCOOH salt, 1.7g, 6.49mmol) add triethylamine (9.74mmol) in the suspension in methyl alcohol (100mL), add tetrahydrochysene-4H-pyrans-4-ketone (9.74mmol) and sodium cyanoborohydride (13.0mmol) then.This mixture is spent the night 50 ℃ of stirrings.Add the tetrahydrochysene-4H-pyrans-4-ketone (3.25mmol) of another part and sodium cyanoborohydride (6.49mmol) and spend the night 50 ℃ of stirrings.Under reduced pressure remove and desolvate, resistates is absorbed in the methylene dichloride (100mL), with saturated sodium bicarbonate (20mL) washing, uses dried over sodium sulfate.Removing desolvates obtains crude product (1.84g, 94%), and it need not to be further purified and can use.MS(M+1)：302.25。
Step B:5-allyl group-8-nitro-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5, the preparation of 9b-six hydrogen-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201703
At 0 ℃, with 8-nitro-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles (5.0mmol) were handled 30 minutes in DMF (20mL) with 60%NaH (10.0mmol), added allyl bromide 98 (6.0mmol) then.Treat that after stirred overnight at room temperature solvent removed in vacuo also is dissolved in methylene dichloride (80mL) with resistates, dried over sodium sulfate is used in water (20mL) washing.Removing desolvates obtains crude product, and this crude product obtains required product by flash chromatography (10-80%EtOAc/ methylene dichloride) purifying, and it is brown oil (1.62g, 95%).MS(M+1)：342.04。The sample that is used for biological test is further purified by reversed-phase HPLC, obtains tfa salt, and it is a pale yellow powder. 1H?NMR(600MHz，CDCl 3)δppm?1.86(m，2H)，2.07(m，2H)，2.98(m，1H)，3.35(m，1H)，3.54(m，4H)，3.76(t，J＝11.78Hz，1H)，3.95(m，1H)，4.20(m，2H)，4.29(m，1H)，4.73(s，2H)，4.80(d，J＝17.15Hz，1H)，5.22(d，J＝10.24Hz，1H)，5.93(m，1H)，7.33(d，J＝8.86Hz，1H)，8.16(d，J＝8.86Hz，1H)，8.41(s，1H)。
Embodiment 181.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) benzsulfamide
Figure BSA00000321451201711
Steps A: 2-cyclopentyl-5-propyl group-2,3,4,4a, 5, the preparation of 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine
To 5-allyl group-2-cyclopentyl-8-nitro-2,3,4,4a, 5, (490mg, 1.51mmol) (1: 1v/v 30mL) in the solution in, adds 10%Pd/C (50mg) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles in ethyl acetate/methanol.With this mixture room temperature (40psi) hydrogenation 5 hours.After filtering and concentrating, obtain crude product (403mg, 90%), it is an oily matter.MS(M+1)：298.33。
The preparation of step B:N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) benzsulfamide
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5, (30mg 0.1mmol) adds benzene sulfonyl chloride (0.11mmol) in the solution in anhydrous methylene chloride (2mL) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine, adds triethylamine (0.2mmol) then.With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (10mL), and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (36mg, 65%) of required product by the reversed-phase HPLC purifying.MS(M+1)：438.0。 1H?NMR(600MHz，CDCl 3)δppm?0.88(t，J＝7.34Hz，3H)，1.72(m，4H)，1.91(m，2H)，2.13(m，4H)，2.95(m，1H)，3.34(m，1H)，3.46(m，1H)，3.61(m，1H)，3.93(m，3H)，4.10(m，1H)，4.70(m，1H)，6.81(d，J＝8.80Hz，1H)，6.86(s，1H)，7.11(d，J＝8.80Hz，1H)，7.18(s，1H)，7.41(t，J＝7.63Hz，2H)，7.52(m，1H)，7.71(d，J＝7.63Hz，2H)。
Embodiment 182.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopropane sulphonamide
Figure BSA00000321451201722
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] (30mg 0.1mmol) adds cyclopropane SULPHURYL CHLORIDE (0.11mmol) to indoles-8-amine in the solution in anhydrous methylene chloride (2mL), then add triethylamine (0.2mmol).With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (10mL), and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (32mg, 61%) of required product by the reversed-phase HPLC purifying.MS(M+1)：402.0。 1H?NMR(600MHz，CDCl 3)δppm?0.85-1.01(m，4H)，1.15(m，2H)，1.69(m，2H)，1.78(m，2H)，1.4-1.99(m，3H)，2.15(m，4H)，2.47(m，1H)，2.98(m，1H)，3.36(m，1H)，3.50(m，1H)，3.63(m，1H)，3.92-4.05(m，3H)，4.16(d，J＝13.75Hz，1H)，4.79(d，J＝13.75Hz，1H)，6.41(s，1H)，7.14(d，J＝8.45Hz，1H)，7.27(d，J＝8.45Hz，1H)，7.36(s，1H)。
Embodiment 183.N '-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N, N-dimethyl methyl acid amides
Figure BSA00000321451201731
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] (30mg 0.1mmol) adds dimethylamino SULPHURYL CHLORIDE (0.11mmol) to indoles-8-amine in the solution in anhydrous acetonitrile (2mL), then add triethylamine (0.2mmol).Reaction mixture is spent the night 50 ℃ of stirrings.Add methylene dichloride (10mL), and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (23mg, 45%) of required product by the reversed-phase HPLC purifying.MS(M+1)：405.0。 1H?NMR(600MHz，CDCl 3)δppm?0.92(t，J＝7.04Hz，3H)，1.68(m，2H)，1.78(m，2H)，1.91(m，2H)，2.00-2.38(m，4H)，2.84(s，6H)，2.97(m，1H)，3.37(m，1H)，3.48(m，1H)，3.62(m，1H)，4.00(m，3H)，4.17(m，1H)，4.77(m，1H)，6.58(s，1H)，7.12(d，J＝8.22Hz，1H)，7.24(d，J＝8.22Hz，1H)，7.31(s，1H)。
Embodiment 184.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) ethyl sulfonamide
Figure BSA00000321451201732
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5, (30mg 0.1mmol) adds ethyl sulfonyl chloride (0.11mmol) in the solution in anhydrous methylene chloride (2mL) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine, then adds triethylamine (0.2mmol).With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (10mL) and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (28mg, 56%) of required product by the reversed-phase HPLC purifying.MS(M+1)：390.0。 1H?NMR(600MHz，CDCl 3)δppm?0.91(t，J＝7.21Hz，3H)，1.40(t，J＝7.04Hz，3H)，1.69(m，1H)，1.77(m，1H)，1.90(m，2H)，2.03(m，4H)，2.17(m，2H)，2.98(m，1H)，3.10(q，J＝7.04Hz，2H)，3.34(m，1H)，3.52(m，1H)，3.61(m，1H)，4.00(m，3H)，4.15(m，1H)，4.78(m，1H)，6.49(s，1H)，7.06(d，J＝8.80Hz，1H)，7.25(d，J＝8.80Hz，1H)，7.33(s，1H)。
Embodiment 185.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) benzamide
Figure BSA00000321451201741
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5, (30mg 0.1mmol) adds Benzoyl chloride (0.11mmol) in the solution in anhydrous methylene chloride (2mL) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine, then adds triethylamine (0.2mmol).With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (10mL) and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (33mg, 63%) of required product by the reversed-phase HPLC purifying.MS(M+1)：402.0。 1H?NMR(600MHz，CDCl 3)δppm?0.92(t，J＝7.30Hz，3H)，1.67(m，2H)，1.79(m，2H)，1.89(m，2H)，2.07(m，1H)，2.16(m，3H)，2.99(m，1H)，3.42(m，2H)，3.60(m，1H)，4.01(m，3H)，4.19(m，1H)，4.76(m，1H)，7.28(m，1H)，7.29(s，1H)，7.52(m，2H)，7.58(m，1H)，7.92(m，3H)，8.01(s，1H)。
Embodiment 186.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) propionic acid amide
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5, (30mg 0.1mmol) adds propionyl chloride (0.11mmol) in the solution in anhydrous methylene chloride (2mL) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine, then adds triethylamine (0.2mmol).With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (10mL) and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (29mg, 62%) of required product by the reversed-phase HPLC purifying.MS(M+1)：354.0。 1H?NMR(600MHz，CDCl 3)
Figure BSA00000321451201751
ppm?0.90(t，J＝7.14Hz，3H)，1.29(t，J＝7.41Hz，3H)，1.66(m，2H)，1.77(m，2H)，1.90(s，2H)，2.13(m，4H)，2.43(m，2H)，2.97(m，1H)，3.40(m，2H)，3.58(m，1H)，3.97(m，3H)，4.16(m，1H)，4.71(m，1H)，7.15(d，J＝8.51Hz，1H)，7.23(d，J＝8.51Hz，1H)，7.39(s，1H)，7.77(s，1H)。
Embodiment 187.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopropane carboxamide
Figure BSA00000321451201752
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] (30mg 0.1mmol) adds cyclopropanecarbonyl chloride (0.11mmol) in the solution in anhydrous methylene chloride (2mL) to indoles-8-amine, then adds triethylamine (0.2mmol).With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (10mL) and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (36mg, 75%) of required product by the reversed-phase HPLC purifying.MS(M+1)：366.0。 1H?NMR(600MHz，CDCl 3) ppm?0.83-0.95(m，5H)，1.10(m，2H)，1.56(m，1H)，1.67(m，2H)，1.77(m，2H)，1.90(m，2H)，1.99-2.16(m，4H)，2.96(m，1H)，3.38(m，2H)，3.58(m，1H)，3.97(m，3H)，4.14(m，1H)，4.70(m，1H)，7.15(d，J＝8.68Hz，1H)，7.22(d，J＝8.68Hz，1H)，7.62(s，1H)，7.78(s，1H)。C 23H 31N 3O1.5C 2HF 3O 2The analytical calculation value: C, 58.20; H, 6.10; N, 7.83.Measured value: C, 58.03; H, 5.89; N, 8.28.
Embodiment 188.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopentane formamide
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] (30mg 0.1mmol) adds pentamethylene formyl chloride (0.11mmol) to indoles-8-amine in the solution in anhydrous methylene chloride (2mL), add triethylamine (0.2mmol) then.With reaction mixture in stirred overnight at room temperature.Add methylene dichloride (10mL) and, use dried over sodium sulfate this solution with water (10mL) washing.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (28mg, 55%) of required product by the reversed-phase HPLC purifying.MS(M+1)：394.0。 1H?NMR(600MHz，CDCl 3)δppm?0.90(t，J＝7.27Hz，3H)，1.58-1.72(m，4H)，1.73-1.86(m，4H)，1.86-2.02(m，6H)，2.02-2.18(m，4H)，2.72(m，1H)，2.96(m，1H)，3.41(m，2H)，3.58(m，1H)，3.98(m，3H)，4.15(m，1H)，4.71(m，1H)，7.13(d，J＝8.65Hz，1H)，7.23(d，J＝8.65Hz，1H)，7.36(s，1H)，7.83(s，1H)。
Embodiment 189.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N '-ethyl carbamide
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5, (30mg 0.1mmol) adds ethyl isocyanate (0.11mmol) in the solution in dry DMF (2mL) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine, then adds triethylamine (0.2mmol).With reaction mixture in stirred overnight at room temperature.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (28mg, 58%) of required product by the reversed-phase HPLC purifying.MS(M+1)：369.0。 1H?NMR(600MHz，CD 3OD)δppm?0.94(t，J＝7.34Hz，3H)，1.17(t，J＝7.34Hz，3H)，1.75-1.95(m，8H)，2.33(m，2H)，3.25(m，4H)，3.56(m，1H)，3.82(m，1H)，4.00(m，1H)，4.10(m，2H)，4.39(d，J＝13.50Hz，1H)，4.71(d，J＝13.50Hz，1H)，7.03(d，J＝8.55Hz，1H)，7.35(d，J＝8.55Hz，1H)，7.59(s，1H)。
Embodiment 190.N-cyclopentyl-N '-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) urea
Figure BSA00000321451201771
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5, (30mg 0.1mmol) adds cyclic isocyanate pentyl ester (0.11mmol) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine in the solution in dry DMF (2mL), add triethylamine (0.2mmol) then.With reaction mixture in stirred overnight at room temperature.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (26mg, 69%) of required product by the reversed-phase HPLC purifying.MS(M+1)：409.0。 1H?NMR(600MHz，CD 3OD)
Figure BSA00000321451201772
ppm?0.94(t，J＝7.34Hz，3H)，1.25(t，J＝7.04Hz，2H)，1.48(m，1H)，1.65(m，1H)，1.70-1.84(m，7H)，1.85-2.00(m，5H)，2.33(m，2H)，3.23(m，2H)，3.56(m，1H)，3.82(m，1H)，4.00(m，1H)，4.10(m，3H)，4.39(d，J＝14.09Hz，1H)，4.70(d，J＝13.50Hz，1H)，7.01(d，J＝8.80Hz，1H)，7.34(d，J＝8.80Hz，1H)，7.60(s，1H)。
Embodiment 191.N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N '-phenylurea
Figure BSA00000321451201773
To thick 2-cyclopentyl-5-propyl group-2,3,4,4a, 5, (30mg 0.1mmol) adds phenylcarbimide (0.11mmol) in the solution in dry DMF (2mL) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-amine, adds triethylamine (0.2mmol) then.With reaction mixture in stirred overnight at room temperature.Removing desolvates obtains crude product, and this crude product obtains the tfa salt (32mg, 60%) of required product by the reversed-phase HPLC purifying.MS(M+1)：417.0。 1H?NMR(600MHz，CD 3OD)δppm?0.95(t，J＝7.34Hz，3H)，1.70-1.95(m，6H)，2.34(m，2H)，3.25(m，2H)，3.57(m，2H)，3.82(m，1H)，4.00(m，1H)，4.11(m，3H)，4.40(d，J＝13.50Hz，1H)，4.74(d，J＝14.09Hz，1H)，7.03(m，1H)，7.10(d，J＝8.56Hz，1H)，7.30(t，J＝7.63Hz，2H)，7.39(d，J＝8.56Hz，1H)，7.45(d，J＝7.63Hz，2H)，7.71(s，1H)。
Embodiment 192.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(benzenesulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201781
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-5-(benzenesulfonyl)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201782
Under nitrogen atmosphere, to 2-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid (196mg, 0.493mmol) and potassium tert.-butoxide (123mg, 1.10mmol) drip in the solution in dry DMF (5mL) benzene sulfonyl chloride (90 μ l, 0.70mmol).This mixture stirring at room 1 hour, is added H then 2O (15ml) collects solid and dry, obtains crude product (256mg).MS(M+1)：538.21。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(benzenesulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt
Figure BSA00000321451201783
In room temperature, to 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(benzenesulfonyl)-1,3; 4; (256mg 0.476mmol) adds trifluoroacetic acid (1ml) in the solution in methylene dichloride (5ml) to 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester.With this solution stirring at room 30 minutes.Solvent removed in vacuo and excessive trifluoroacetic acid obtain the tfa salt (280mg) of required product.MS(M+1)：437.96。
Step C:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(benzenesulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201791
To 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(benzenesulfonyl)-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] and the indoles tfa salt (250mg, 0.453mmol), tetrahydrochysene-4H-pyrans-4-ketone (150mg; 1.50mmol) add in the solution in methylene dichloride (5ml) sodium triacetoxy borohydride (215mg, 1.01mmol).This mixture stirred under nitrogen atmosphere spend the night, add 1N NaOH (2ml) then and this mixture was stirred 1 minute.Reaction mixture is diluted with methylene dichloride (20ml), and the organic layer process is the Hydromatrix tube (10g) of filling in advance, and washs with methylene dichloride (20ml).This methylene dichloride of vacuum concentration, resistates is by preparation HPLC (10-70%CH 3CN, 30 minutes) purifying, obtain the tfa salt (85mg) of title compound.MS(M+1)：521.92。 1H?NMR(400MHz，CD 3OD)δppm?0.96(d，J＝6.45Hz，3H)，1.03-1.26(m，2H)，1.48-1.95(m，5H)，2.12(d，J＝10.16Hz，2H)，2.83(t，J＝12.30Hz，1H)，2.98-3.15(m，1H)，3.31-3.76(m，7H)，3.82-4.14(m，3H)，4.33-4.75(m，3H)，7.41(d，J＝8.59Hz，1H)，7.47-7.57(m，3H)，7.65(t，J＝7.32Hz，1H)，7.93(d，J＝8.01Hz，2H)，8.21(d，J＝8.79Hz，1H)。
Embodiment 193.2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } methyl benzoate
Figure BSA00000321451201792
Steps A: 5-{[2-(methoxycarbonyl) phenyl] alkylsulfonyl }-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201801
Under nitrogen atmosphere; to 2-(tert-butoxycarbonyl)-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid (202mg, 0.508mmol) and potassium tert.-butoxide (112mg; 1.00mmol) drip in the solution in dry DMF (5mL) 90% (2-chlorosulfonyl) methyl benzoate (258mg, 0.989mmol).This mixture stirring at room 1.5 hours, is added H then 2O (15ml) collects solid and dry, obtains crude product, and it does not have purifying just to use.MS(M+1)：595.93。
Step B:2-({ 8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyridine is [4,3-b] indoles-5-yl also } alkylsulfonyl) preparation of methyl benzoate tfa salt
Figure BSA00000321451201802
In room temperature; to the thick 5-{[2-of steps A (methoxycarbonyl) phenyl] alkylsulfonyl }-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4; add trifluoroacetic acid (2ml) in the solution of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester in methylene dichloride (5ml).With this solution in stirred overnight at room temperature.Vacuum is removed excessive TFA and methylene dichloride, and with the resistates freeze-drying, obtains crude product, and it does not have purifying just to use.MS(M+1)：495.92。
Step C:2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } preparation of methyl benzoate
Figure BSA00000321451201811
According to identical method described in the embodiment 192 step C, by 2-({ 8-[(4-methyl piperidine-1-yl) carbonyl]-1,2; 3; 4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } alkylsulfonyl) methyl benzoate tfa salt and tetrahydrochysene-4H-pyrans-4-ketone, the tfa salt of preparation title compound.MS(M+1)：579.90。 1H?NMR(400MHz，CD 3OD)δppm?0.94(d，J＝7.03Hz，3H)，1.00-1.26(m，2H)，1.38-1.96(m，4H)，2.14(d，J＝12.50Hz，2H)，2.70-3.14(m，2H)，3.31-3.77(m，7H)，3.77-4.03(m，1H)，3.89(s，3H)，4.09(d，J＝11.72Hz，3H)，4.53(d，3H)，7.33(d，J＝8.59Hz，1H)，7.43-7.59(m，2H)，7.61(s，1H)，7.67-7.77(m，2H)，7.92(d，J＝8.59Hz，1H)。
Embodiment 194.2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } phenylformic acid
Figure BSA00000321451201812
To 2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1; 2; 3; 4-tetrahydrochysene-5H-pyrido [4; 3-b] indoles-5-yl] alkylsulfonyl } methyl benzoate tfa salt (21mg; 0.036mmol) add 1N NaOH (0.5mL) in the solution in methyl alcohol (1mL), and this mixture was stirred 2 hours.Solvent removed in vacuo, and resistates is dissolved in H once more 2O (1mL) adds acetate (0.1mL).This mixture obtains the tfa salt (11mg) of title compound by preparation HPLC (10-70%, 30 minutes) purifying and freeze-drying.MS(M+1)：566.0。 1H?NMR(400MHz，CD 3OD)δppm?0.95(d，J＝6.45Hz，3H)，0.99-1.30(m，2H)，1.40-2.00(m，5H)，2.04-2.21(m，2H)，2.64-3.16(m，2H)，3.33-3.82(m，8H)，4.10(dd，J＝11.62，4.20Hz，2H)，4.41-4.72(m，3H)，7.32(dd，J＝8.59，1.56Hz，1H)，7.54-7.63(m，2H)，7.65-7.76(m，3H)，7.92(d，J＝8.59Hz，1H)。
Embodiment 195.2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } the methyl benzoate tfa salt
Figure BSA00000321451201821
According to the identical method of embodiment 192 step C, by 2-({ 8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } alkylsulfonyl) methyl benzoate tfa salt and cyclopentanone, the tfa salt of preparation title compound.MS(M+1)：563.88。 1H?NMR(400MHz，CD 3OD)δppm?0.93(t，J＝6.25Hz，3H)，0.99-1.27(m，2H)，1.40-1.97(m，8H)，2.18-2.38(m，2H)，2.70-3.13(m，2H)，3.28-3.67(m，4H)，3.73-4.00(m，3H)，3.82-3.90(m，3H)，4.20-4.79(m，3H)，7.22-7.39(m，1H)，7.40-7.58(m，2H)，7.58-7.65(m，，1H)，7.69(d，J＝5.47Hz，2H)，7.83-7.98(m，1H)。
Embodiment 196.2-cyclobutyl-5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201822
Steps A: alkylsulfonyl 5-[(1-methyl isophthalic acid H-imidazol-4 yl)]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201823
In room temperature, (98mg 0.875mmol) adds to 2-(tert-butoxycarbonyl)-2,3,4, and (202mg is 0.508mmol) in the solution in dry DMF (3mL) for 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid with potassium tert.-butoxide.With this mixture stirring at room 5 minutes, drip then 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE (142mg, 0.788mmol).With reaction mixture stirring at room 1 hour, with 1N NaOH (1mL) cancellation and add H 2O (10mL).Collect solid and dry, obtain crude product, this crude product obtains required product (155mg) through silica gel purification.MS(M+1)：541.93。
Step B:5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt
Figure BSA00000321451201831
According to the identical method of embodiment 192 step B, by 5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3; 4; 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester prepares the tfa salt of required product.MS(M+1)：441.93。
Step C:2-cyclobutyl-5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt
Figure BSA00000321451201832
According to the method that is similar to embodiment 192 step C, by 5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3; 4; 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt and cyclobutanone, the tfa salt of preparation title compound.MS(M+1)：495.98。1HNMR(400MHz，CD 3OD)δppm?0.95(d，J＝6.44Hz，3H)，1.02-1.28(m，2H)，1.40-2.04(m，5H)，2.17-2.53(m，4H)，2.83(t，J＝11.23Hz，1H)，2.98-3.17(m，1H)，3.23-4.00(m，6H)，3.68(s，3H)，4.13(d，J＝13.09Hz，1H)，4.47-4.72(m，2H)，7.34(dd，J＝8.78，1.56Hz，1H)，7.52(d，J＝0.98Hz，1H)，7.65(s，1H)，8.06(d，J＝8.79Hz，1H)，8.07(s，1H)。
Embodiment 197.5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201841
According to the method that is similar to embodiment 192 step C, by 5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3; 4; 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt and tetrahydrochysene-4H-pyrans-4-ketone, the tfa salt of preparation title compound.MS(M+1)：526.96。1HNMR(400MHz，CD 3OD)δppm?0.94(d，J＝6.25Hz，3H)，1.00-1.26(m，2H)，1.36-1.80(m，3H)，1.79-1.94(m，2H)，2.13(d，J＝10.94Hz，2H)，2.66-3.15(m，2H)，3.34-3.80(m，10H)，3.82-4.16(m，3H)，4.31-4.73(m，3H)，7.32(d，J＝8.59Hz，1H)，7.53(s，1H)，7.63(s，1H)，8.04(d，J＝8.59Hz，1H)，8.05(s，1H)。
Embodiment 198.8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201842
Steps A: 8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201843
According to identical HATU coupling method described in embodiment 145 steps A, the preparation title compound, by 2-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid and 3,4-dihydro different quinoline-2 (1H)-quinoline.MS(M+1)：
Step B:8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(ethylsulfonyl)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Under 0 ℃, to 8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] add in the solution of the Indoline-2-carboxylic acid tert-butyl ester (0.8mmol) in dry DMF (5mL) NaH (60%, 4.0mmol) and at uniform temp stirred 30 minutes.Add ethyl sulfonyl chloride (2.4mmol) then and in stirred overnight at room temperature.Remove and desolvate, and resistates is absorbed in the methylene dichloride (30mL), Na is used in water and salt water washing 2SO 4Dry and concentrated.Crude product obtains required product (305mg, 73%) by purification by flash chromatography.MS(M+1)：524.0。
Step C:8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201852
With intermediate 8-(3,4-dihydro-isoquinoline-2 (1H)-Ji the carbonyl)-5-(ethylsulfonyl)-1,3,4 of preceding step, 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (0.1mmol) are at room temperature 4NHCl/ two
Figure BSA00000321451201853
Alkane (2mL) was handled 2 hours, was evaporated to dried then.Thick HCl salt is handled in methylene dichloride (3mL) with tetrahydrochysene-4H-pyrans-4-ketone (0.2mmol) and sodium triacetoxy borohydride (0.2mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (14mg, 22%) of required product.MS(M+1)：508.0。 1H?NMR(400MHz，CD 3OD)δppm?1.23(t，J＝7.32Hz，3H)，1.78-2.00(m，2H)，2.08-2.22(m，2H)，2.83-3.04(m，2H)，3.40-3.58(m，10H)，3.61-3.79(m，2H)，3.91-4.05(m，1H)，4.11(dd，J＝11.43，3.61Hz，2H)，4.44-4.76(m，2H)，7.05-7.27(m，4H)，7.49(d，J＝8.69Hz，1H)，7.71(s，1H)，8.07(d，J＝8.69Hz，1H)。
Embodiment 199.8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(ethylsulfonyl)-2-(tetrahydrofuran (THF)-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
With intermediate 8-(3,4-dihydro-isoquinoline-2 (1H)-Ji the carbonyl)-5-(ethylsulfonyl)-1,3,4 of embodiment 198 steps A, 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (0.1mmol) are at room temperature 4N HCl/ two
Figure BSA00000321451201862
Alkane (2mL) was handled 2 hours, was evaporated to dried then.Thick HCl salt is handled in methylene dichloride (3mL) with dihydrofuran-3 (2H)-ketone (0.2mmol) and sodium triacetoxy borohydride (0.2mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Na is used in solution (5mL) washing 2SO 4Dry.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (9mg, 15%) of required product.MS(M+1)：494.0。 1HNMR(400MHz，CD 3OD)δppm?1.23(t，J＝7.32Hz，3H)，2.26-2.37(m，1H)，2.44-2.58(m，1H)，2.84-3.03(m，2H)，3.40-3.56(m，6H)，3.61-3.84(m，4H)，3.92(m，2H)，4.08-4.18(m，1H)，4.18-4.33(m，2H)，4.51-4.72(m，2H)，7.08-7.26(m，4H)，7.49(d，J＝8.61Hz，1H)，7.70(s，1H)，8.07(d，J＝8.61Hz，1H)。
Embodiment 200.8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-2-(1-methyl piperidine-4-yl)-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201863
Steps A: 8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(sulfonyl propyl base)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201871
Under 0 ℃, to 8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-1,3,4, add t-BuOK (0.48mmol) in the solution of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (0.24mmol) in dry DMF (2mL) and stirred 10 minutes at uniform temp.Add third SULPHURYL CHLORIDE (0.6mmol) then and in stirred overnight at room temperature.Remove and desolvate, resistates is absorbed in the methylene dichloride (30mL), and Na is used in water and salt water washing 2SO 4Drying concentrates.Crude product need not to be further purified and promptly can be used for next step.MS(M+1)：538.0。
Step B:8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-2-(1-methyl piperidine-4-yl)-5-(sulfonyl propyl base)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201872
Thick 8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(sulfonyl propyl base)-1,3 with preceding step; 4; 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester was dissolved in methylene dichloride (5mL) and handles with TFA (1mL), stirring at room 2 hours.To be evaporated after do, thick tfa salt is handled in methylene dichloride (5mL) with 1-methyl piperidine-4-ketone (0.4mmol) and sodium triacetoxy borohydride (0.4mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (20mL) dilution, is used saturated NaHCO 3Solution (10mL) washing, and use Na 2SO 4Dry.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (29mg, three step 16%) of required product.MS(M+1)：535.0。 1H?NMR(400MHz，CD 3OD)δppm?0.95(t，J＝7.42Hz，3H)，1.60-1.73(m，2H)，2.11-2.27(m，2H)，2.45-2.59(m，2H)，2.82-3.01(m，3H)，2.90(s，3H)，3.08-3.21(m，2H)，3.38-3.50(m，4H)，3.63-3.81(m，7H)，4.54-4.67(m，3H)，7.05-7.26(m，4H)，7.48(d，J＝8.59Hz，1H)，7.68(s，1H)，8.06(d，J＝8.59Hz，1H)。
Embodiment 201.5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201881
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
To 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester (796mg 2.0mmol) adds TFA (3mL) in the solution in methylene dichloride (20mL), and with reaction mixture stirring at room 3 hours.After concentrating, resistates is handled in methylene dichloride (30mL) with tetrahydrochysene-4H-pyrans-4-ketone (6.0mmol) and sodium triacetoxy borohydride (6.0mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (50mL) dilution, is used saturated NaHCO 3Solution (20mL) washing, and use Na 2SO 4Dry.With this solution for vacuum concentration, resistates obtains required product by purification by flash chromatography, and it is brown oil (650mg, 86%).MS(M+1)：382.0。
Step B:5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201883
Under 0 ℃, to 8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (80mg, 0.21mmol) add in the solution in dry DMF (5mL) NaH (60%, 0.42mmol) and in uniform temp stirred 30 minutes.Whole then part of ground adds 3-(imidazoles-1-alkylsulfonyl)-1-methyl-3H-imidazoles-1-fluoroform sulphonate (triflate) and (0.42mmol) and 80 ℃ of stirrings spends the night.Except that desolvating and resistates being absorbed in the methylene dichloride (20mL), Na is used in water and salt solution extraction 2SO 4Drying concentrates.Crude product reversed-phase HPLC purifying obtains product 63mg (41%).MS(M+1)：512.0。 1H?NMR(400MHz，CD 3OD)δppm?0.96(d，J＝6.45Hz，3H)，1.04-1.30(m，2H)，1.48-1.82(m，3H)，1.83-1.97(m，2H)，2.08-2.23(m，2H)，2.77-2.94(m，1H)，3.01-3.16(m，1H)，3.39-3.57(m，5H)，3.55-3.84(m，3H)，3.86-4.01(m，1H)，4.11(dd，J＝11.43，3.22Hz，2H)，4.46-4.73(m，2H)，7.00-7.67(m，4H)，8.07-8.91(m，2H)。
Embodiment 202.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(morpholine-4-base carbonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201891
Under 0 ℃, to 8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, add in the solution of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (0.2mmol) in dry DMF (3mL) NaH (60%, 0.4mmol) and at uniform temp stirred 30 minutes.Add morpholine-4-formyl chloride (0.4mmol) then and in stirred overnight at room temperature.Except that desolvating and resistates being absorbed in methylene dichloride (20mL), Na is used in water and salt solution extraction 2SO 4Drying concentrates.Crude product obtains tfa salt 39mg (32%) by the reversed-phase HPLC purifying.MS(M+1)：495.0。 1H?NMR(400MHz，CD 3OD)δppm0.96(d，J＝6.45Hz，3H)，1.04-1.29(m，2H)，1.51-1.82(m，3H)，1.84-1.98(m，2H)，2.11-2.22(m，2H)，2.76-2.95(m，1H)，3.02-3.17(m，1H)，3.42-3.61(m，7H)，3.63-3.75(m，5H)，3.75-3.86(m，3H)，3.93-4.04(m，1H)，4.11(dd，J＝11.43，3.61Hz，2H)，4.43-4.55(m，1H)，4.54-4.64(m，1H)，4.66-4.78(m，1H)，7.36(d，J＝8.00Hz，1H)，7.54(d，J＝8.00Hz，1H)，7.62(s，1H)。
Embodiment 203.5-[(5-methyl is different
Figure BSA00000321451201892
Azoles-4-yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201901
Under room temperature and nitrogen atmosphere, with 60%NaH (16mg 0.4mmol) whole part adds to 8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] (75mg is 0.2mmol) in the suspension in DMF (2mL) for indoles.This mixture was stirred 30 minutes, different at room temperature adding 5-methyl
Figure BSA00000321451201902
Azoles-4-SULPHURYL CHLORIDE (54mg, 0.3mmol), and with reaction mixture stirring at room 2 hours.Solvent removed in vacuo also is dissolved in methylene dichloride with resistates and washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product, and this crude product is by reversed-phase HPLC (10-75%CH 3CN) purifying is used the MeOH recrystallization then, obtains title compound (4.5mg).MS(M+1)：527.0。 1H?NMR(400MHz，DMSO-D 6)δppm?0.92(d，J＝6.25Hz，3H)，0.99-1.16(m，2H)，1.49-1.85(m，7H)，2.08-2.14(m，2H)，2.69-3.08(m，2H)，3.27-3.45(m，8H)，3.56-3.79(m，2H)，3.88-3.98(m，1H)，4.01(dd，J＝11.33，3.71Hz，2H)，4.34-4.52(m，1H)，4.56-4.67(m，1H)，7.26(d，J＝8.59，1H)，7.58(s，1H)，7.87(d，J＝8.40Hz，1H)，9.85(bs，1H)。
Embodiment 204.2-cyclopentyl-5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201903
Steps A: 5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201911
Under 0 ℃, to 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4, add in the solution of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (2.0mmol) in dry DMF (15mL) NaH (60%, 10.0mmol) and in uniform temp stirred 30 minutes.Whole then part of ground adds 3-(imidazoles-1-alkylsulfonyl)-1-methyl-3H-imidazoles-1-fluoroform sulphonate, and (6.0mmol, preparation method see Serge Beaudoin, Kenneth E.Kinsey and James F.Bums; J.Org.Chem., 2003,68 (1); 115), and at 80 ℃ stirred 6 hours.Except that desolvating and resistates being absorbed in methylene dichloride (50mL), Na is used in water and salt solution extraction 2SO 4Drying concentrates.Crude product obtains product (203mg, 19%) by the reversed-phase HPLC purifying.MS(M+1)：528.39。
Step B:2-cyclopentyl-5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201912
With 5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4; 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester (60mg, 0.114mmol) at 1M HCl (in diethyl ether; solution 3mL) forms white precipitate in stirred overnight at room temperature.Except that after desolvating, solid is absorbed in the methylene dichloride (3mL) also with cyclopentanone (0.23mmol) and sodium triacetoxy borohydride (0.23mmol) processing.This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Solution (5mL) washing, and use Na 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (11mg) of required product.MS(M+1)：496.0。 1H?NMR(400MHz，CD 3OD)δppm?0.96(d，J＝6.45Hz，3H)，1.05-1.34(m，2H)，1.51-1.96(m，9H)，2.21-2.36(m，2H)，2.74-2.93(m，1H)，3.01-3.19(m，1H)，3.40-3.66(m，3H)，3.70-3.85(m，2H)，3.88-4.01(m，1H)，4.28-4.42(m，1H)，4.53-4.65(m，1H)，4.65-4.77(m，1H)，6.99-7.28(m，1H)，7.46-7.66(m，3H)，8.07-8.44(m，2H)。
Embodiment 205.N-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide
Figure BSA00000321451201921
Steps A: 1-({ 2-(tert-butoxycarbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } alkylsulfonyl)-preparation of 3-methyl isophthalic acid H-imidazoles-3-fluoroform sulphonate
Figure BSA00000321451201922
At 0 ℃; with 5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1; 3; 4; 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester (60mg, 0.114mmol) solution in anhydrous acetonitrile (2mL) adds to the trifluoromethanesulfonic acid methyl esters in anhydrous acetonitrile (0.1M; 1.25mL) in solution in, stirred 1 hour at uniform temp then.After the evaporation, crude product need not to be further purified and promptly can be used for next step.MS(M+1)：542.00。
Step B:5-[(ethylamino) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201923
To thick 1-({ 2-(tert-butoxycarbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1; 2; 3; 4-tetrahydrochysene-5H-pyrido [4; 3-b] indoles-5-yl } alkylsulfonyl)-add 2M ethamine/THF (0.5mmol) in the 3-methyl isophthalic acid H-imidazoles-solution of 3-fluoroform sulphonate (0.1mmol) in anhydrous acetonitrile (3mL), then in stirred overnight at room temperature.After the evaporation, crude product need not to be further purified and promptly can be used for next step.MS(M+1)：505.25。
Step C:N-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide
Figure BSA00000321451201931
Thick 5-[(ethylamino with preceding step) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester is at room temperature 4N HCl/ two
Figure BSA00000321451201932
Alkane (2mL) was handled 2 hours, was evaporated to dried then.Thick HCl salt is handled in methylene dichloride (3mL) with tetrahydrochysene-4H-pyrans-4-ketone (0.2mmol) and sodium triacetoxy borohydride (0.2mmol).This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Solution (5mL) washing, and use Na 2SO 4Dry.With this dichloromethane solution vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (3.0mg, four step 4.4%) of required product.MS(M+1)：489.0。
Embodiment 206.5-(ethylsulfonyl)-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201933
Steps A: 1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2, the preparation of 8-dicarboxylic acid 8-benzyl ester 2-tertiary butyl ester
With 2-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid (2g, 6.33mmol) be dissolved in DMF (40mL) and 0 ℃ add DBU (0.95mL, 6.35mmol).Drip then bromotoluene (0.75mL, 6.30mmol).Stirred reaction mixture, till not observing any raw material, concentrating under reduced pressure then.Then with this mixture diluted in methylene dichloride, water and salt water washing, dry and concentrating under reduced pressure.With resistates recrystallization in MeOH, obtain white solid (1.72g, 67%) then.MS(M+1)：407.1。
Step B:5-(ethylsulfonyl)-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2, the preparation of 8-dicarboxylic acid 8-benzyl ester 2-tertiary butyl ester
Figure BSA00000321451201942
Under room temperature and nitrogen atmosphere, with 60%NaH (350mg 8.75mmol) adds to 1,3,4 wholely part, 5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2, (1.12g is 2.76mmol) in the suspension in DMF (17mL) for 8-dicarboxylic acid 8-benzyl ester 2-tertiary butyl ester.This mixture was stirred 30 minutes, room temperature add ethyl chloride (500 μ L, 5.28mmol), and with this mixture stirring at room 2 hours.Solvent removed in vacuo, and resistates is dissolved in methylene dichloride, wash with water, use dried over sodium sulfate.Removing desolvates obtains crude product.MS(M+1)：490.9。
Step C:2-(tert-butoxycarbonyl)-5-(ethylsulfonyl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid
Figure BSA00000321451201943
The thick 5-(ethylsulfonyl)-1,3,4 that previous step is rapid, 5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2,8-dicarboxylic acid 8-benzyl ester 2-tertiary butyl ester is dissolved in MeOH, and adds the 10%Pd/C of catalytic amount.This mixture hydrogenation is spent the night.After the filtration, under reduced pressure remove and desolvate.MS：408.8。
Step D:5-(ethylsulfonyl)-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201951
In room temperature; to 2-(tert-butoxycarbonyl)-5-(ethylsulfonyl)-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles-8-carboxylic acid (0.88mmol), in diisopropyl ethyl amine (1.06mmol) and the solution of 4-methoxyl group piperidines (1.06mmol) in DMF (4mL), add HATU (1.06mmol).Stirring at room several hours, concentrating under reduced pressure was diluted in the methylene dichloride then, and uses saturated NaHCO successively with this mixture 3The aqueous solution, water and salt water washing.Removal of solvent under reduced pressure obtains thick amide intermediate, and it does not have purifying just to use.MS(M+1)：506.0。
Step e: 5-(ethylsulfonyl)-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201952
According to identical method described in the embodiment 192 step B, by thick 5-(ethylsulfonyl)-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester prepares the tfa salt of required product.MS(M+1)：406.9。
Step F: 5-(ethylsulfonyl)-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451201953
With sodium triacetoxy borohydride (60mg; 0.57mmol) add to 5-(ethylsulfonyl)-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles TFA (100mg, 0.19mmol) and tetrahydrochysene-4H-pyrans-4-ketone (70 μ L are 0.76mmol) in the mixture in methylene dichloride (3mL).With this mixture in stirring at room.Add sodium triacetoxy borohydride (60mg) and tetrahydrochysene-4H-pyrans-4-ketone (35 μ L) once more, to finish reaction.Then this mixture is diluted with methylene dichloride, use saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.Crude product is by reversed-phase HPLC (5-75%CH 3CN) purifying obtains two tfa salts of required product, and it is white solid (36mg, 30%).MS(M+1)：490.0。 1H?NMR(400MHz，CD 3OD)δppm?1.06(t，J＝7.32Hz，3H)，1.30-1.60(m，3H)，1.62-1.91(m，4H)，2.04(d，J＝10.35Hz，2H)，3.22(s，3H)，3.25-3.54(m，11H)，3.54-3.65(m，1H)，3.79-4.00(m，1H)，3.98(dd，J＝11.72，4.10Hz，2H)，4.13-4.69(m，2H)，7.28(d，J＝8.69，1H)，7.52(s，1H)，7.89(d，J＝8.59Hz，1H)。
Embodiment 207. (1-{[2-cyclobutyl-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidin-4-yl) methyl alcohol
Figure BSA00000321451201961
Steps A: 5-(ethylsulfonyl)-8-{[4-(hydroxymethyl) piperidines-1-yl] carbonyl }-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201962
According to embodiment 206 step D in similar method, by 2-(tert-butoxycarbonyl)-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid and piperidines-4-methyl alcohol, preparation title compound.MS(M+1)：506.0。
Step B: trifluoroacetic acid 1-{[5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidin-4-yl) preparation of methyl ester
Figure BSA00000321451201963
According to identical method described in the embodiment 192 step B, by 5-(ethylsulfonyl)-8-{[4-(hydroxymethyl) piperidines-1-yl] carbonyl-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester, the preparation title compound tfa salt.MS(M+1)：502.2。
Step C:(1-{[2-cyclobutyl-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidin-4-yl) preparation of methyl alcohol
Figure BSA00000321451201971
With sodium triacetoxy borohydride (130mg; 0.61mmol) add to trifluoroacetic acid (1-{[5-(ethylsulfonyl)-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles-8-yl] carbonyl piperidin-4-yl) methyl esters TFA (160mg, 0.32mmol) and cyclobutanone (48 μ L are 0.64mmol) in the mixture in methylene dichloride (3mL).This mixture stirring at room several hours, is added other sodium triacetoxy borohydride (76mg) then to finish reaction.Then this mixture is diluted with methylene dichloride, and with saturated NaHCO 3Solution washing is used Na 2SO 4Dry also concentrating under reduced pressure.Crude product is by reversed-phase HPLC (5-75%CH 3CN) purifying obtains two tfa salts of required product, and it is white solid (36mg, 24%).MS(M+1)：460.0。 1H?NMR(400MHz，CD 3OD)δppm?0.99-1.18(m，2H)，1.03(t，J＝7.32Hz，3H)，1.45-1.86(m，5H)，2.32-2.40(m，4H)，2.63-2.82(m，1H)，2.86-3.04(m，1H)，3.11-3.40(m，8H)，3.50-3.73(m，2H)，3.74-3.88(m，1H)，3.90-4.12(m，1H)，4.41-4.66(m，2H)，7.24(d，J＝8.79，1H)，7.46(s，1H)，7.86(d，J＝8.79Hz，1H)。
Embodiment 208.1-{[2-cyclobutyl-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidines-4-alcohol
Figure BSA00000321451201972
Steps A: 5-(ethylsulfonyl)-8-[(4-hydroxy piperidine-1-yl) carbonyl]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201981
According to embodiment 206 step D in similar method, by 2-(tert-butoxycarbonyl)-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-carboxylic acid and piperidines-4-alcohol, preparation title compound.MS(M+1)：492.0。
Step B:1-{[5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } preparation of piperidines-4-carboxylic acid methyl ester trifluoroacetate
Figure BSA00000321451201982
According to identical method described in the embodiment 192 step B, by 5-(ethylsulfonyl)-8-[(4-hydroxy piperidine-1-yl) carbonyl]-1,3; 4; 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester prepares the tfa salt of title compound and pure accordingly together.MS (M+1): 488.2 and 392.2.
Step C:(1-{[2-cyclobutyl-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidin-4-yl) methyl alcohol
Figure BSA00000321451201983
According to the method that is similar to embodiment 207 step C; by the rapid crude product of previous step (1-{[5-(ethylsulfonyl)-2; 3; 4; 5-tetrahydrochysene-1H-pyrido [4; 3-b] indoles-8-yl] carbonyl } mixture of piperidines-4-carboxylic acid trifluoro methyl esters TFA and correspondent alcohol thereof) and cyclobutanone, the tfa salt of preparation title compound.MS(M+1)：460.0。 1H?NMR(400MHz，CD 3OD)δppm?1.16(t，J＝7.42Hz，3H)，1.34-1.61(m，2H)，1.69-1.83(m，1H)，1.84-1.99(m，3H)，2.27-2.49(m，4H)，3.17-3.51(m，6H)，3.44(q，J＝7.42Hz，2H)，3.54-3.69(m，1H)，3.70-3.82(m，1H)，3.82-3.98(m，2H)，4.06-4.22(m，2H)，4.60-4.73(m，1H)，7.37(dd，J＝8.59，1.56Hz，1H)，7.60(s，1H)，7.99(d，J＝8.59Hz，1H)。
Embodiment 209.N-[5-(methyl sulphonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] cyclopentane formamide
Figure BSA00000321451201991
Steps A: 5-(methyl sulphonyl)-8-nitro-1,3,4,4a, 5, the preparation of 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201992
Under room temperature and nitrogen atmosphere, with 60%NaH (110mg 2.75mmol) adds to 8-nitro-1,3,4 wholely part, 4a, 5, (600mg is 1.89mmol) in the suspension in DMF (10mL) for 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester.This mixture was stirred 30 minutes, and (170 μ L 2.19mmol), and make reaction mixture be warming up to room temperature to add Methanesulfonyl chloride at 0 ℃.Solvent removed in vacuo also is dissolved in methylene dichloride with resistates, washes with water, uses dried over sodium sulfate.Removing desolvates obtains crude product, and it is used for next step without purifying.MS(M+1)：396.9。
Step B:8-amino-5-(methyl sulphonyl)-1,3,4,4a, 5, the preparation of 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451201993
With thick 5-(methyl sulphonyl)-8-nitro-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester is dissolved in THF (15mL) and adds 10%Pd/C (60mg).Reaction mixture hydrogenation is spent the night.Then this mixture is filtered and concentrating under reduced pressure.MS(M+1)：366.9。
Step C:8-[(cyclopentylcarbonyl) amino]-5-(methyl sulphonyl)-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451202001
To 8-amino-5-(methyl sulphonyl)-1,3,4,4a, 5, add triethylamine (1.3mmol) in the solution of 9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (0.8mmol) in methylene dichloride (10mL).Drip pentamethylene formyl chloride (0.92mmol) at 0 ℃ then.Reaction stirred is not till observing any raw material.With also water and the salt water washing in methylene dichloride of this mixture diluted, dry and concentrating under reduced pressure.
Step D:N-[5-(methyl sulphonyl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] cyclopentane formamide
According to identical method described in the embodiment 192 step B, by the 8-[(cyclopentylcarbonyl) amino]-5-(methyl sulphonyl)-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester prepares the tfa salt of required product.MS(M+1)：362.0。
Step e: N-[5-(methyl sulphonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] preparation of cyclopentane formamide
Figure BSA00000321451202003
According to the method that is similar to embodiment 208 step C, by N-[5-(methyl sulphonyl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] cyclopentane formamide and tetrahydrochysene-4H-pyrans-4-ketone, the tfa salt of preparation title compound.MS(M+1)：446.0。 1H?NMR(400MHz，CD 3OD)δppm?1.51-1.92(m，11H)，2.08(d，J＝10.74Hz，2H)，2.73(q，J＝7.88Hz，1H)，3.12(s，3H)，3.25-3.47(m，1H)，3.41(t，J＝11.23Hz，3H)，3.57-3.70(m，1H)，4.03(dd，J＝11.62，4.20Hz，2H)，4.35-4.58(m，2H)，7.23(dd，J＝8.98，1H)，7.81(d，J＝8.98Hz，1H)，7.90(s，1H)。
Embodiment 210.N-[5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] tetramethyleneimine-1-methane amide
Figure BSA00000321451202011
Steps A: 5-(ethylsulfonyl)-8-nitro-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451202012
Under 0 ℃,, add t-BuOK (6.0mmol) in the solution of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (3.0mmol) in dry DMF (10mL), and stirred 10 minutes in uniform temp to 8-nitro-1,3,4.Add ethyl sulfonyl chloride (6.0mmol) then and in stirring at room 3 hours.Except that desolvating and resistates being absorbed in methylene dichloride (40mL), Na is used in water and salt solution extraction 2SO 4Drying concentrates, and obtains crude product, and it is yellow solid (1.15g, 94%).MS(M+1)：410.0。
Step B:8-amino-5-(ethylsulfonyl)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
In the presence of room temperature and 10%Pd/C, with 5-(ethylsulfonyl)-8-nitro-1,3,4, the hydrogenation 2 hours under 40psi of the solution of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl esters (1.0mmol) in methyl alcohol (30mL).After the filtration, obtain crude benzol amine, it is Off-white solid (368mg, 97%), and this solid need not to be further purified and promptly can be used for next step.MS(M+1)：380.0。
Step C:5-(ethylsulfonyl)-8-[(tetramethyleneimine-1-base carbonyl) amino]-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451202021
To 8-amino-5-(ethylsulfonyl)-1; 3; 4; 5-tetrahydrochysene-2H-pyrido [4; 3-b] add tetramethyleneimine-1-formyl chloride (0.45mmol) in the solution of the Indoline-2-carboxylic acid tert-butyl ester (0.3mmol) in anhydrous acetonitrile (5mL); then add triethylamine (0.45mmol), reaction mixture is spent the night 80 ℃ of stirrings.After concentrating, resistates is absorbed in the methylene dichloride (30mL), uses saturated NaHCO 3Na is used in solution (10mL) washing 2SO 4Dry.With this solution for vacuum concentration, resistates obtains required product by purification by flash chromatography, and it is oily matter (132mg, 92%).MS(M+1)：477.0。
Step D:N-[5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl]-preparation of tetramethyleneimine-1-methane amide
Figure BSA00000321451202022
To 5-(ethylsulfonyl)-8-[(tetramethyleneimine-1-base carbonyl) amino]-1; 3,4,5-tetrahydrochysene-2H-pyrido [4; 3-b] add TFA (1mL) in the solution of the Indoline-2-carboxylic acid tert-butyl ester (0.28mmol) in methylene dichloride (5mL), and with reaction mixture stirring at room 3 hours.After concentrating, should handle in methylene dichloride (5mL) with tetrahydrochysene-4H-pyrans-4-ketone (0.56mmol) and sodium triacetoxy borohydride (0.56mmol) by thick tfa salt.This mixture in stirred overnight at room temperature, with methylene dichloride (20mL) dilution, is used saturated NaHCO 3Na is used in solution (10mL) washing 2SO 4Dry.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (84mg, 52%) of required product.MS(M+1)：461.0。 1H?NMR(400MHz，CD 3OD)δppm?1.17(t，J＝7.42Hz，3H)，1.81-1.93(m，2H)，1.96(t，J＝6.44Hz，4H)，2.09-2.20(m，2H)，3.36-3.54(m，11H)，3.64-3.76(m，1H)，3.92-4.05(m，1H)，4.11(dd，J＝11.62，4.00Hz，2H)，4.42-4.54(m，1H)，4.55-4.67(m，1H)，7.27(dd，J＝8.98，1.95Hz，1H)，7.69(d，J＝1.95Hz，1H)，7.83(d，J＝8.98Hz，1H)。
Embodiment 211.N-[5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide
Figure BSA00000321451202031
Steps A: 5-(ethylsulfonyl)-8-{[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl] amino }-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
Figure BSA00000321451202032
To 8-amino-5-(ethylsulfonyl)-1; 3; 4; 5-tetrahydrochysene-2H-pyrido [4; 3-b] add 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE (0.32mmol) in the solution of the Indoline-2-carboxylic acid tert-butyl ester (0.26mmol) in anhydrous methylene chloride (8mL), then add triethylamine (0.52mmol), with reaction mixture in stirred overnight at room temperature; and, use saturated NaHCO with methylene dichloride (20mL) dilution 3Na is used in solution (10mL) washing 2SO 4Dry.With this solution for vacuum concentration, crude product need not to be further purified and promptly can be used for next step.MS(M+1)：524.0。
Step B:N-[5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl]-preparation of 1-methyl isophthalic acid H-imidazoles-4-sulphonamide
Figure BSA00000321451202033
To thick 5-(ethylsulfonyl)-8-{[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl] amino }-1; 3; 4; 5-tetrahydrochysene-2H-pyrido [4; 3-b] add TFA (0.5mL) in methylene dichloride (3mL) solution of the Indoline-2-carboxylic acid tert-butyl ester (0.26mmol), and with reaction mixture stirring at room 3 hours.After concentrating, should handle in methylene dichloride (5mL) with tetrahydrochysene-4H-pyrans-4-ketone (0.52mmol) and sodium triacetoxy borohydride (0.52mmol) by thick tfa salt.This mixture in stirred overnight at room temperature, with methylene dichloride (20mL) dilution, is used saturated NaHCO 3Solution (10mL) washing, and use Na 2SO 4Dry.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (38mg, three step 21%) of required product.MS(M+1)：508.0。 1H?NMR(400MHz，CD 3OD)δppm?1.16(t，J＝7.32Hz，3H)，1.80-2.00(m，2H)，2.09-2.21(m，2H)，3.40(q，J＝7.29Hz，4H)，3.44-3.54(m，3H)，3.66(s，3H)，3.68-3.76(m，1H)，3.87-4.05(m，1H)，4.08-4.16(m，2H)，4.39-4.54(m，1H)，4.56-4.72(m，1H)，7.06(dd，J＝8.95，2.00Hz，1H)，7.46(d，J＝2.00Hz，1H)，7.60(s，1H)7.64(s，1H)，7.77(d，J＝8.95Hz，1H)。
Embodiment 212. (trans-4-{[(2-cyclopentyl-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) amino] carbonyl } cyclohexyl) t-butyl carbamate
Figure BSA00000321451202041
To 2-cyclopentyl-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] add [trans-4-(aminocarboxyl) cyclohexyl] t-butyl carbamate (0.89mmol) in the indoles-solution of 8-amine (0.74mmol) in DMF (8mL), then add HATU (0.89mmol) and diisopropyl ethyl amine (0.89mmol), with reaction mixture stirring at room 3 hours.After concentrating, resistates is absorbed in the methylene dichloride (50mL), uses saturated NaHCO 3Na is used in solution (10mL) and salt solution (10mL) extraction 2SO 4Drying concentrates.Crude product (353mg, 91%) need not to be further purified and promptly can be used for next step.The crude product of part obtains tfa salt by the reversed-phase HPLC purifying.MS(M+1)：523.0。 1H?NMR(400MHz，CD 3OD)δppm?0.90(t，J＝7.42Hz，3H)，1.18-1.33(m，2H)，1.41(s，9H)，1.52-1.69(m，2H)，1.71-1.83(m，5H)，1.83-2.04(m，8H)，2.22-2.36(m，2H)，3.17-3.24(m，3H)，3.46-3.59(m，1H)，3.79(t，J＝7.71Hz，1H)，3.96(d，J＝12.11Hz，1H)，4.02-4.13(m，2H)，4.35(d，J＝14.06Hz，1H)，4.67(d，J＝14.06Hz，1H)，7.09-7.14(m，1H)，7.34(d，J＝8.79Hz，1H)，7.80(d，J＝1.76Hz，1H)。
Embodiment 213. trans-N-(2-cyclopentyl-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl)-4-[(2,2-dimethyl propylene acyl group) amino] cyclohexane carboxamide
Figure BSA00000321451202051
Thick (trans-4-{[(2-cyclopentyl-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) amino that will be in EtOAc (5mL)] carbonyl cyclohexyl) t-butyl carbamate (0.15mmol) in room temperature with 4N HCl/ two
Figure BSA00000321451202052
Alkane (1mL) was handled 5 hours, was evaporated to dried then.Should handle in methylene dichloride (3mL) with cyclopentanone (0.3mmol) and sodium triacetoxy borohydride (0.3mmol) by thick HCl salt.This mixture in stirred overnight at room temperature, with methylene dichloride (15mL) dilution, is used saturated NaHCO 3Solution (5mL) washing, and use Na 2SO 4Dry.With this solution for vacuum concentration, resistates reversed-phase HPLC purifying obtains the tfa salt (28mg, 30%) of required product.MS(M+1)：507.0。 1H?NMR(400MHz，CD 3OD)δppm?0.90(t，J＝7.42Hz，3H)，1.15(s，9H)，1.26-1.49(m，2H)，1.61-1.85(m，8H)，1.85-2.00(m，7H)，2.25-2.38(m，2H)，3.15-3.23(m，2H)，3.45-3.59(m，1H)，3.61-3.73(m，1H)，3.79(t，J＝7.81Hz，1H)，3.92-4.01(m，1H)，4.03-4.13(m，2H)，4.35(d，J＝14.06Hz，1H)，4.67(d，J＝14.06Hz，1H)，7.11(dd，J＝8.75，1.80Hz，1H)，7.34(d，J＝8.75Hz，1H)，7.80(d，J＝1.80Hz，1H)。
Embodiment 214.N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] cyclohexane carboxamide
Figure BSA00000321451202053
Steps A: 5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-amine
Figure BSA00000321451202061
To 5-allyl group-8-nitro-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5, (1.6g, 4.69mmol) (1: 1v/v 50mL) adds 10%Pd/C (200mg) to 9b-six hydrogen-1H-pyrido [4,3-b] indoles in the solution in ethyl acetate/methanol.This mixture is spent the night in room temperature (40psi) hydrogenation.After filtering and concentrating, slightly produced v thing (1.28g, 87%), it is an oily matter.MS(M+1)：314.07。
Step B:N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] preparation of cyclohexane carboxamide
Figure BSA00000321451202062
To 5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] add hexahydrobenzoic acid (0.3mmol) in the indoles-solution of 8-amine (0.25mmol) in dry DMF (3mL), add diisopropyl ethyl amine (0.3mmol) and HATU (0.3mmol) then.With this mixture stirring at room 3 hours.Solvent removed in vacuo, resistates water (10mL) are handled and with methylene dichloride (2x20mL) extraction, are used Na 2SO 4Drying, evaporation.Resistates reversed-phase HPLC purifying obtains the tfa salt (54mg, 40%) of required product.MS(M+1)：426.0。 1H?NMR(400MHz，CD 3OD)δppm0.86(t，J＝7.03Hz，3H)，1.17-1.40(m，3H)，1.42-1.57(m，2H)，1.61-1.95(m，9H)，2.05-2.19(m，2H)，2.25-2.42(m，1H)，3.12-3.22(m，3H)，3.33-3.57(m，3H)，3.58-3.73(m，1H)，3.89-4.01(m，1H)，4.02-4.17(m，3H)，4.34-4.50(m，1H)，4.52-4.66(m，1H)，7.07-7.14(m，1H)，7.27-7.35(m，1H)，7.73-7.80(m，1H)。
Embodiment 215-218: the following examples according to the preparation of method identical described in the embodiment 214 step B.
Figure BSA00000321451202063
Figure BSA00000321451202071
Embodiment 219.8-[(4-methyl piperidine-1-yl) carbonyl]-5-(pyridine-2-ylmethyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451202081
Steps A: carbonyl 8-[(4-methyl piperidine-1-yl)]-5-(pyridine-2-ylmethyl)-1,3,4, the preparation of 5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester
According to be similar to embodiment 135 the method for steps A, by 8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester and 2-(chloromethyl) pyridine, preparation title compound.MS(M+1)：489.14。
Step B:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(pyridine-2-ylmethyl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451202083
According to the method that is similar to embodiment 135 step B, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(pyridine-2-ylmethyl)-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] the Indoline-2-carboxylic acid tert-butyl ester, preparation title compound.MS(M+1)：389.06。
Step C:8-[(4-methyl piperidine-1-yl) carbonyl]-5-(pyridine-2-ylmethyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4, the preparation of 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
According to the method that is similar to embodiment 135 step B, by 8-[(4-methyl piperidine-1-yl) carbonyl]-5-(pyridine-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles and tetrahydrochysene-4H-pyrans-4-ketone, the tfa salt of preparation title compound.
MS(MS+1)：473.0。 1H?NMR(600MHz，CDCl 3)δppm?0.87-1.30(m，5H)，1.41-1.84(m，3H)，1.92-2.05(m，2H)，2.06-2.19(m，2H)，2.73-3.20(m，4H)，3.26-3.39(m，1H)，3.46(t，J＝11.25Hz，2H)，3.54-3.72(m，2H)，3.73-3.87(m，1H)，4.13(d，J＝8.78Hz，2H)，4.21-4.36(m，1H)，4.49-4.66(m，2H)，5.47-5.63(m，2H)，6.93-7.11(m，3H)，7.35-7.44(m，1H)，7.54-7.64(m，1H)，7.99-8.10(m，1H)，8.55-8.67(m，1H)。
Embodiment 220.5-(ethylsulfonyl)-2-(1-methyl piperidine-4-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451202091
According to the method that is similar to embodiment 99 step C, by 5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt and 1-methyl piperidine-4-ketone, preparation title compound.MS(MS+1)：487.0。 1H?NMR(400MHz，CD 3OD)δppm?0.98(d，J＝6.45Hz，3H)，1.07-1.28(m，2H)，1.18(t，J＝7.32Hz，3H)，1.54-1.86(m，3H)，2.21-2.39(m，2H)，2.56(d，J＝12.69Hz，2H)，2.80-2.98(m，1H)，2.92(s，3H)，3.04-3.27(m，1H)，3.19(t，J＝12.40Hz，2H)，3.41-3.52(m，4H)，3.63-3.90(m，6H)，4.57-4.69(m，3H)，7.40(d，J＝8.59Hz，1H)，7.62(d，J＝1.17Hz，1H)，8.02(d，J＝8.59Hz，1H)。
Embodiment 221.5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000321451202092
According to being similar to the method described in the embodiment 89 step C, by dihydrofuran-3 (the 2H)-ketone of embodiment 91 steps A and 5-allyl group-8-[(4-methyl piperidine-1-yl of embodiment 1 step D) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt, the preparation title compound.MS(M+1)：408.0。 1H NMR (400MHz, and the δ ppm 0.99 of methyl alcohol-D4) (d, J=6.64Hz, 3H), 1.06-1.31 (m, 2H), and 1.48-1.89 (m, 3H), 2.25-2.42 (m, 1H), and 2.47-2.60 (m, 1H), 2.76-2.98 (m, 1H), and 2.99-3.17 (m, 1H), 3.19-3.26 (m, 2H), and 3.64-3.89 (m, 1H), 3.79 (q, J=8.01Hz, 3H), 3.91-4.03 (m, 1H), 4.15 (dt, J=8.69,4.10Hz, 1H), 4.21-4.39 (m, 3H), 4.34-4.77 (m, 2H), 4.34-4.77 (m, 3H), 5.15 (d, J=10.55Hz, 1H), and 5.90-6.06 (m, 1H), 7.25 (d, J=8.59Hz, 1H), 7.46 (d, J=8.40Hz, 1H), 7.59 (d, J=0.98Hz, 1H).

Claims (10)

1. formula I compound or its pharmacy acceptable salt, diastereomer, enantiomer or its mixture:
Figure FSA00000321451100011
Wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8With-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl, C 1-6Alkyl, C 1-6Thiazolinyl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heteroaryl-C 1-4Alkyl ,-C (=O)-C 1-6Alkyl ,-C (=O)-C 3-6Cycloalkyl and-C (=NH)-C 1-6Alkyl is optional to be selected from following group by one or more and to replace :-OR, R, NO 2,-CO 2H ,-CO 2-R;-SO 2-R; Halogen;-OH;-NH 2-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl;
R 4Be selected from nitrogenous C 3-9Heterocyclic radical and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclic radical can be chosen wantonly and is selected from following group by one or more and replace: C 1-6Alkyl, phenyl, C 1-6Alkoxyl group ,-NH 2,-OH, halo C 1-6Alkyl and halogen; And
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl.
2. according to the compound of claim 1, wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8,-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from C 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, and oxyethyl group ,-S (=O) 2CH 3, methyl, ethyl ,-NO 2,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl and C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-C 1-4Alkyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-C 1-4Alkyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, and oxyethyl group ,-S (=O) 2CH 3, methyl, ethyl ,-NO 2,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 4Be selected from nitrogenous C 3-9Heterocyclylalkyl and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclylalkyl can be chosen wantonly and is selected from following group by one or more and replace: methyl, ethyl, phenyl, methoxyl group, oxyethyl group ,-OH, trifluoromethyl and halogen; And
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, phenyl, benzyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-methyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-methyl; Hydroxyl-C 1-6Alkyl, methoxyl group-C 1-6Alkyl and oxyethyl group-C 1-6Alkyl.
3. according to the compound of claim 1, wherein
R 1Be selected from-C (=O)-R 4With-NH-C (=O)-R 5
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl, benzyl and C 3-5Heteroaryl-methyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-C (=O)-C 1-6Alkyl, benzyl and C 3-5Heteroaryl-methyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group ,-NO 2,-S (=O) 2CH 3, methyl, ethyl ,-CO 2H ,-CO 2CH 3,-CO 2CH 2CH 3And halogen;
R 3Be selected from C 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-methyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-methyl and C 1-6Alkyl wherein defines R 3The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Heterocyclylalkyl-methyl, C 3-6Cycloalkyl, C 3-6Cycloalkyl-methyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen;
R 4Be selected from piperidyl, piperazinyl and morpholinyl, wherein said piperidyl, piperazinyl and morpholinyl be optional to be selected from following group by one or more and to replace: methyl, ethyl, methoxyl group, oxyethyl group ,-OH, methylol, trifluoromethyl and halogen; And
R 9And R 10Be independently selected from :-H, C 1-6Alkyl and C 2-6Thiazolinyl.
4. according to the compound of claim 1, wherein
Figure FSA00000321451100031
Figure FSA00000321451100041
Figure FSA00000321451100051
R 2Be selected from methyl, ethyl, the 1-propyl group, the 2-propyl group, the 1-butyl, the 2-butyl, the tertiary butyl, allyl group ,-S (=O) 2-CH 3,-S (=O) 2-CH 2CH 3, 2-methoxy ethyl, tetrahydropyran-4-base-methyl, 1-sulfonyl propyl base, cyclopropyl alkylsulfonyl, phenyl, benzenesulfonyl, 2-(methoxycarbonyl)-benzenesulfonyl; 2-(hydroxycarbonyl group)-benzenesulfonyl, 1-methyl isophthalic acid H-imidazol-4 yl-alkylsulfonyl, 1H-imidazoles-1-base-alkylsulfonyl, (the 5-methyl is different Azoles-4-yl) alkylsulfonyl, morpholine-4-base carbonyl, 4-amino-phenyl ,-CH 2-C (=O)-N (CH 3) 2,-C (=O)-N (CH 3) 2,-S (=O) 2-N (CH 3) 2,-S (=O) 2-NHCH 2CH 3,-C (=O)-CH 2CH 2CH 3,-CH 2-C (=O)-OCH 3,-CH 2-C (=O)-OCH 2CH 3,-CH 2-CO 2H, benzyl, 4-aminobenzyl; the 4-nitrobenzyl, 4-methyl sulphonyl-benzyl, 4-methylthio group-benzyl; 4-acetylaminohydroxyphenylarsonic acid benzyl, 4-methoxyl group-benzyl, 4-oxyethyl group-benzyl; 2,6-difluorobenzyl, (6-chloro-1; 3-benzodioxole-5-yl) methyl, (5-ethoxy carbonyl)-furans-2-base-methyl, (2-methyl isophthalic acid; 3-thiazole-4-yl)-and methyl, (5-methyl-different
Figure FSA00000321451100053
Azoles-4-yl)-and methyl, pyridine-2-ylmethyl, cyclobutylmethyl and cyclopropyl methyl;
R 3Be selected from ethyl, sec.-propyl, propyl group, 2-methyl-propyl group; the 1-butyl, 1-amyl group, 1-ethanoyl-piperidin-4-yl, tetramethylene sulfide-3-base; the cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclobutyl; cyclopentyl, cyclohexyl, 4-tetrahydrochysene-2H-pyranyl, tetrahydrochysene-thiapyran-4-base; the 2-pyrimidyl, 1-imino-ethyl, 2-pyridyl, 3; 4,5,6-tetrahydropyridine-2-base; 3,4-dihydro-2 h-pyrrole-5-base, 2-pyridyl-methyl; the 3-pyridylmethyl, 4-pyridylmethyl, 1-methyl-4-piperidyl; the 4-piperidyl, (6-methyl-pyridine-2-yl) methyl, (2-ethyl-4-methyl isophthalic acid H-imidazoles-5-yl) methyl; tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, tetrahydrofuran (THF)-3-ylmethyl; 1-ethyl-1H-pyrazoles-4-base, 1,3-dimethyl-1H-pyrazoles-5-base; (3-picoline-4-yl) methyl, 1,3-
Figure FSA00000321451100054
Azoles-2-ylmethyl, 1,3-
Figure FSA00000321451100055
Azoles-5-ylmethyl, 2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl, tetrahydrochysene-2H-pyrans-4-ylmethyl, 2-phenylethyl, 2-methoxy-benzyl, 3,3,3-trifluoro propyl, 2,2-two fluoro ethyls, 2-hydroxycyclopent base, (1-ethyl-3-methyl isophthalic acid H-pyrazoles-5-yl) methyl, 2,1,3-benzo
Figure FSA00000321451100056
Diazole-5-ylmethyl, 3-thienyl methyl, 2-trifluoromethyl-benzyl; the 3-methyl butyl, hexamethylene-3-alkene-1-ylmethyl, 2-fluoro-6-methoxy-benzyl; 2-phenyl-propyl group, 2-ethyl-butyl, cyclobutyl carbonyl; 2,2-difluoro propionyl, cyclopentylcarbonyl; tetrahydrochysene-2H-pyrans-4-base carbonyl, cyclopropyl carbonyl, propyl group carbonyl; N-ethylamino carbonyl, N-sec.-propyl aminocarboxyl, cyclopropyl alkylsulfonyl and ethylsulfonyl.
5. according to the compound of claim 1, wherein
R 1Be selected from
Figure FSA00000321451100061
R 2Be selected from-H, methyl, ethyl, the 1-propyl group, the 2-propyl group, the 1-butyl, the 2-butyl, the tertiary butyl, allyl group ,-S (=O) 2-CH 3,-S (=O) 2-CH 2CH 3, 2-methoxy ethyl, tetrahydropyran-4-base-methyl, 1-sulfonyl propyl base, cyclopropyl alkylsulfonyl, phenyl, benzenesulfonyl, 2-(methoxycarbonyl)-benzenesulfonyl; 2-(hydroxycarbonyl group)-benzenesulfonyl, 1-methyl isophthalic acid H-imidazol-4 yl-alkylsulfonyl, 1H-imidazoles-1-base-alkylsulfonyl, (the 5-methyl is different
Figure FSA00000321451100062
Azoles-4-yl) alkylsulfonyl, morpholine-4-base carbonyl, 4-amino-phenyl,
-CH 2-C (=O)-N (CH 3) 2,-C (=O)-N (CH 3) 2,-S (=O) 2-N (CH 3) 2,-S (=O) 2-NHCH 2CH 3,-C (=O)-CH 2CH 2CH 3,-CH 2-C (=O)-OCH 3,-CH 2-C (=O)-OCH 2CH 3,-CH 2-CO 2H, benzyl, 4-aminobenzyl; the 4-nitrobenzyl, 4-methyl sulphonyl-benzyl, 4-methylthio group-benzyl; 4-acetylaminohydroxyphenylarsonic acid benzyl, 4-methoxyl group-benzyl, 4-oxyethyl group-benzyl; 2,6-difluorobenzyl, (6-chloro-1; 3-benzodioxole-5-yl) methyl, (5-ethoxy carbonyl)-furans-2-base-methyl, (2-methyl isophthalic acid; 3-thiazole-4-yl)-and methyl, (5-methyl-different
Figure FSA00000321451100063
Azoles-4-yl)-and methyl, pyridine-2-ylmethyl, cyclobutylmethyl and cyclopropyl methyl; And
R 3Be selected from ethyl, sec.-propyl, propyl group, 2-methyl-propyl group; the 1-butyl, 1-amyl group, 1-ethanoyl-piperidin-4-yl; tetramethylene sulfide-3-base, cyclopropyl methyl, cyclobutylmethyl; cyclopentyl-methyl, cyclobutyl, cyclopentyl; cyclohexyl, 4-tetrahydrochysene-2H-pyranyl, tetrahydrochysene-thiapyran-4-base; 1-imino-ethyl, 3,4; 5,6-tetrahydropyridine-2-base, 3; 4-dihydro-2 h-pyrrole-5-base, tetrahydrofuran (THF)-3-ylmethyl, tetrahydrofuran (THF)-2-base; tetrahydrofuran (THF)-3-base, 1-methyl-4-piperidyl, 2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl; tetrahydrochysene-2H-pyrans-4-ylmethyl, 3,3; the 3-trifluoro propyl, 2,2-two fluoro ethyls; 2-hydroxycyclopent base, 3-methyl butyl, hexamethylene-3-alkene-1-ylmethyl and 2-ethyl-butyl.
6. compound, it is selected from:
5-allyl group-2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(1-ethanoyl piperidin-4-yl)-5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-3-thienyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(cyclopentyl-methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-cyclohexyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-thiapyran-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-amyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridine-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[(6-picoline-2-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridin-3-yl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridin-4-yl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(2-ethyl-4-methyl isophthalic acid H-imidazoles-5-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(3-methyl butyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(hexamethylene-3-alkene-1-ylmethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2-fluoro-6-methoxy-benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(2-phenyl propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2-ethyl-butyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-butyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(1-ethyl-1H-pyrazoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(1,3-dimethyl-1H-pyrazoles-5-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[(3-picoline-4-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(1,3-
Figure FSA00000321451100081
Azoles-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(2-phenylethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2-methoxy-benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(1-ethyl-3-methyl isophthalic acid H-pyrazoles-5-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2,1, the 3-benzo
Figure FSA00000321451100082
Diazole-5-ylmethyl)-and 8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-[(1-ethyl-3-methyl isophthalic acid H-pyrazoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3-thienyl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[2-(trifluoromethyl) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-piperidin-4-yl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(2,2-difluoro propionyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(cyclopentylcarbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-base carbonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(cyclopropyl carbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-N-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] indoles-2-methane amide;
5-allyl group-N-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,4a, 5,9b-six hydrogen-2H-pyrido [4,3-b] indoles-2-methane amide;
5-allyl group-2-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridine-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[(6-picoline-2-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(1,3-
Figure FSA00000321451100091
Azoles-5-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(1,3-
Figure FSA00000321451100101
Azoles-2-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-ethyl-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-[2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopentyl-methyl)-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridin-3-yl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-2-(3-methyl butyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(hexamethylene-3-alkene-1-ylmethyl)-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-butyl-5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(pyridin-4-yl methyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-amyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2-methoxy ethyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(2-phenylethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(tetrahydrofuran (THF)-3-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(2,2-two fluoro ethyls)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
(1R*, 2R*)-2-{8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b] indoles-2-yl } cyclopentanol;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-pyridine-2-base-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2-(3,4,5,6-tetrahydropyridine-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(3,4-dihydro-2 h-pyrrole-5-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclobutyl carbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopentylcarbonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(2,2-difluoro propionyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-2-isobutyl--8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclobutyl-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclobutyl carbonyl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-pyrimidine-2-base-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3,4,5,6-tetrahydropyridine-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
1-{5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-1,3,4,5-tetrahydrochysene-2H-pyrido [4,3-b1 indoles-2-yl } ethyliminum;
2-(3,4-dihydro-2 h-pyrrole-5-yl)-5-(4-ethoxy benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles tfa salt;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(3,4-dihydro-2 h-pyrrole-5-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(methyl sulphonyl)-2-(3,3, the 3-trifluoro propyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(cyclopropyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclobutyl-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(cyclopropyl methyl)-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-(2,2-two fluoro ethyls)-5-(ethylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(sec.-propyl alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(3,3, the 3-trifluoro propyl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
2-cyclopentyl-N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
2-cyclobutyl-N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide;
2-cyclobutyl-N, N-dimethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-methane amide;
5-butyryl radicals-2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-butyryl radicals-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-(cyclopropyl methyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(cyclobutylmethyl)-2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-[(5-methyl is different
Figure FSA00000321451100141
Azoles-4-yl) methyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-the 5-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-{2-cyclobutyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide;
2-{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide;
2-{2-cyclohexyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl }-N,N-dimethylacetamide;
2-cyclobutyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } acetate;
2-cyclohexyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl acetate;
5-(2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl)-the 2-methylfuroate;
5-(2-cyclopentyl-8-[(4-methyl piperidine-1-yl) and carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } methyl)-the 2-furancarboxylic acid;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methylthio group) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles 2-oxide compound;
2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-[4-(methyl sulphonyl) benzyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(4-nitrophenyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
4-[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] phenyl } amine;
N-{4-[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] phenyl } ethanamide;
4-{2-cyclopentyl-8-[(4-methyl piperidine-1-yl) carbonyl]-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl } phenyl) amine;
2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-benzyl-2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-sec.-propyl-5-(4-methoxy-benzyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-amyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-sec.-propyl-8-[(4-methyl piperidine-1-yl) carbonyl]-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-[(6-chloro-1,3-benzodioxole-5-yl) methyl]-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(2, the 6-difluorobenzyl)-2-sec.-propyl-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(4-ethoxy benzyl)-8-[(4-oxyethyl group piperidines-1-yl) carbonyl]-2-sec.-propyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4,4-difluoro piperidines-1-yl) carbonyl]-5-methyl-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-2-(cyclobutyl)-8-[(3-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
1-{[5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidines-4-methane amide;
1-{[5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidines-4-alcohol;
(1-{[5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidin-4-yl) methyl alcohol;
5-methyl-8-[(4-methylpiperazine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-8-(morpholine-4-base carbonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-8-(piperidines-1-base carbonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-(1,4-two oxa-s-8-azaspiro [4.5] decane-8-base carbonyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
N-(1,1-titanium dioxide tetrahydrochysene-3-thienyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
N-[2-(dimethylamino)-2-oxoethyl]-N, 5-dimethyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
N-(2-hydroxyethyl)-N, 5-dimethyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-N-(2-morpholine-4-base ethyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-N, 2-two (tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-N-(pyridin-4-yl methyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
N-(2-methoxy ethyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-N-(tetrahydrofuran (THF)-2-ylmethyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
N-ethyl-5-methyl-N-(pyridin-4-yl methyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-N-phenyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-methane amide;
5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-8-{[4-(trifluoromethyl) piperidines-1-yl] carbonyl }-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-tertiary butyl piperidines-1-yl) carbonyl]-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4,4-lupetidine-1-yl) carbonyl]-5-methyl-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-methyl-8-[(4-Phenylpiperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
N-(5-allyl group-2-cyclopentyl-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N-methyl benzenesulfonamide;
N-methyl-N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] benzsulfamide;
N-[5-allyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl] benzsulfamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) benzsulfamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopropane sulphonamide;
N '-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N, N-dimethyl methyl acid amides;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) ethyl sulfonamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) benzamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) propionic acid amide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopropane carboxamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) cyclopentane formamide;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N '-ethyl carbamide;
N-cyclopentyl-N '-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl) urea;
N-(2-cyclopentyl-5-propyl group-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl)-N '-phenylurea;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(benzenesulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } methyl benzoate;
2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } phenylformic acid;
2-{[8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-yl] alkylsulfonyl } the methyl benzoate tfa salt;
2-cyclobutyl-5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-[(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-5-(ethylsulfonyl)-2-(tetrahydrofuran (THF)-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-(3,4-dihydro-isoquinoline-2 (1H)-Ji carbonyl)-2-(1-methyl piperidine-4-yl)-5-(sulfonyl propyl base)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(morpholine-4-base carbonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
The 5-[(5-methyl is different
Figure FSA00000321451100191
Azoles-4-yl) alkylsulfonyl]-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
2-cyclopentyl-5-(1H-imidazoles-1-base alkylsulfonyl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
N-ethyl-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-1,2,3,4-tetrahydrochysene-5H-pyrido [4,3-b] indoles-5-sulphonamide;
5-(ethylsulfonyl)-8-[(4-methoxyl group piperidines-1-yl) carbonyl]-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
(1-{[2-cyclobutyl-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidin-4-yl) methyl alcohol;
1-{[2-cyclobutyl-5-(ethylsulfonyl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] carbonyl } piperidines-4-alcohol;
N-[5-(methyl sulphonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] cyclopentane formamide;
N-[5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] tetramethyleneimine-1-methane amide;
N-[5-(ethylsulfonyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide;
(trans-4-{[(2-cyclopentyl-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) amino] carbonyl } cyclohexyl) t-butyl carbamate;
Trans-N-(2-cyclopentyl-5-propyl group-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl)-4-[(2,2-dimethyl propylene acyl group) amino] cyclohexane carboxamide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] cyclohexane carboxamide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] tetrahydrochysene-2H-pyrans-4-methane amide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] cyclopentane formamide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] tetrahydrofuran (THF)-2-methane amide;
N-[5-propyl group-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl] the tetramethylene methane amide;
8-[(4-methyl piperidine-1-yl) carbonyl]-5-(pyridine-2-ylmethyl)-2-(tetrahydrochysene-2H-pyrans-4-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-(ethylsulfonyl)-2-(1-methyl piperidine-4-yl)-8-[(4-methyl piperidine-1-yl) carbonyl]-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
5-allyl group-8-[(4-methyl piperidine-1-yl) carbonyl]-2-(tetrahydrofuran (THF)-3-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles;
And pharmacy acceptable salt.
7. be used for the treatment of pain according to each compound in the claim 1～6 in preparation, anxiety disorder, cancer, multiple sclerosis, Parkinson disease, Huntington Chorea, Alzheimer disease, the purposes in the medicine of disorder of gastrointestinal tract and cardiovascular disorder.
8. pharmaceutical composition, it comprises according to each compound and pharmaceutically acceptable carrier in the claim 1～6.
9. the method for a preparation formula II compound comprises:
Figure FSA00000321451100211
Make formula III compound and formula R 11The compound reaction of-CHO,
Figure FSA00000321451100212
Wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8,-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl;
R 4Be selected from nitrogenous C 3-9Heterocyclic radical and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclic radical can be chosen wantonly and is selected from following group by one or more and replace: C 1-6Alkyl, phenyl, C 1-6Alkoxyl group ,-NH 2,-OH, halo C 1-6Alkyl and halogen;
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl; And
R 11Be selected from C 3-6Heterocyclylalkyl, C 3-6Cycloalkyl and C 1-6Alkyl wherein defines R 11The time the described C that uses 3-6Heterocyclylalkyl, C 3-6Cycloalkyl and C 1-6Alkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen.
10. the method for a preparation formula IV compound comprises:
Figure FSA00000321451100221
Make formula III compound and formula
Figure FSA00000321451100222
Compound reaction,
Figure FSA00000321451100223
Wherein
R 1Be selected from-C (=O)-R 4,-NH-C (=O)-R 5,-NH-C (=O)-NH-R 6,-NR 7-S (=O) 2-R 8,-NR 7-S (=O) 2-NR 9R 10
R 2Be selected from-H C 1-6Alkyl, C 2-6Thiazolinyl ,-C (=O)-NR 9R 10,-S (=O) 2-NR 9R 10,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl wherein defines R 2The time the described C that uses 1-6Alkyl, C 2-6Thiazolinyl ,-S (=O) 2-C 1-6Alkyl ,-S (=O) 2-C 6-10Aryl ,-S (=O) 2-C 3-5Heteroaryl ,-C (=O)-C 1-6Alkyl; C 6-10Aryl-C 1-4Alkyl; And C 3-5Heteroaryl-C 1-4Alkyl is optional to be selected from following group by one or more and to replace :-OR, R ,-CO 2H ,-CO 2-R;-SO 2-R; Halogen ,-NO 2,-OH ,-NH 2,-NHR ,-C (=O)-NH 2With-C (=O)-NHR;
R is C 1-6Alkyl;
R 4Be selected from nitrogenous C 3-9Heterocyclic radical and-NR 9R 10, wherein said nitrogenous C 3-9Heterocyclic radical can be chosen wantonly and is selected from following group by one or more and replace: C 1-6Alkyl, phenyl, C 1-6Alkoxyl group ,-NH 2,-OH, halo C 1-6Alkyl and halogen;
R 5, R 6, R 7, R 8, R 9And R 10Be independently selected from :-H, C 1-6Alkyl, C 6-10Aryl, C 6-10Aryl-C 1-4Alkyl, C 3-6Heterocyclic radical, C 3-6Heterocyclic radical-C 1-4Alkyl, C 2-6Thiazolinyl, C 3-6Cycloalkyl and C 3-6Cycloalkyl-C 1-4Alkyl; N, N-two (C 1-4Alkyl) amino-C 1-6Alkyl, hydroxyl-C 1-6Alkyl and C 1-6Alkoxy-C 1-6Alkyl; And
Be selected from C 3-6Heterocyclylalkyl and C 3-6Cycloalkyl, wherein said C 3-6Heterocyclylalkyl and C 3-6Cycloalkyl is optional to be selected from following group by one or more and to replace: methoxyl group, oxyethyl group, methyl, ethyl and halogen.
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